WO2025117674A1

WO2025117674A1 - Compounds for targeted degradation of taf1

Info

Publication number: WO2025117674A1
Application number: PCT/US2024/057660
Authority: WO
Inventors: Justin LOPCHUK; Ernst SCHONBRUNN; Jiandong Chen; Zachary P. SHULTZ
Original assignee: H Lee Moffitt Cancer Center and Research Institute Inc
Current assignee: H Lee Moffitt Cancer Center and Research Institute Inc
Priority date: 2023-11-28
Filing date: 2024-11-27
Publication date: 2025-06-05
Anticipated expiration: 2026-05-28

Abstract

The present disclosure described compounds of Formula I, or pharmaceutically acceptable salts or derivatives thereof, which are degraders of TAF1. Methods of using the compounds in the treatment of medical disorders, such as cancers, are also provided.

Description

Attorney Docket No.10110-450WO1 COMPOUNDS FOR TARGETED DEGRADATION OF TAF1 CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to United States Provisional Patent Application No. 63/603,420 filed November 28, 2023, the disclosure of which is incorporated herein by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT This invention was made with government support under Grant No. CA279378 awarded by the National Institutes of Health. The Government has certain rights in the invention. TECHNICAL FIELD This disclosure relates to compounds useful in treating medical disorders and, more particularly, to compounds for targeted degradation of TAF1 useful in the treatment of cancers. BACKGROUND Transcription initiation by RNA polymerase II requires more than 70 polypeptides, with the basal transcription factor TFIID being the protein that coordinates this activity. TFIID binds to the core promoter to position the polymerase properly, serves as the scaffold for the assembly of the remainder of the transcription complex, and acts as a channel for regulatory signals. TFIID is composed of the TATA-binding protein (TBP) and a group of proteins known as TBP-associated factors, or TAFs, which may participate in basal transcription, serve as coactivators, function in protomer recognition, or modify general transcription factors (GTFs) to facilitate complex assembly and transcription initiation. The TAF1 gene encodes the largest subunit of TFIID. Full-length TFA1 is composed of several domains, including a tandem bromodomain (BRD) module, which performs a wide range of regulatory functions in transcription (see Louder, R. K. et al., Nature 2016, 531-604-609; Wang, H. et al., Cell Res 2014, 1433-1444; Bhattacharya, S. et al., Proc Natl Acad Sci USA 2014, 111, 9103-9108). Attorney Docket No.10110-450WO1 TAF1 protein has been shown to play various roles in oncological disorders. TAF1 binds to Myc oncoprotein and assists in Myc-driven gene transcription (see Wei, Y. et al., Nat Struct Mol Biol 2019, 26, 1035-1043). TAF1 BRD directly interacts with acetylated p53 to initiate the transcription of p53 target genes (see Li, A. G. et al., Molecular Cell 2007, 28, 408-421). TAF1 activates Mdm2-mediated p53 degradation, leading to G1/S cell cycle transition (see Li, H. et al., Molecular Cell 2004, 13, 867-878; Allende-Vega, N. et al., Oncogene 2007, 26, 4234-4242; Cai, X. et al., Proc Natl Acad Sci USA 2008, 105, 16958- 16963). Cell lines with defective TAF1 exhibit hallmarks of an ATR-mediated DNA damage response (see Buchmann, A. M. et al., Mol Cell Bio 2004, 24, 5332-5339). TAF1 is found to be significantly mutated in uterine serous carcinoma (see Hong, B. et al., Curr Opin Genet Dev 2015, 30, 25-31), TAF1 overexpression is a major factor for the high mitotic activity of solid tumors (see Wada, C. et al., Cancer Res 1992, 52, 307-313), and TAF1 BRD function has been implicated in AML1-ETO driven acute myeloid leukemia (see Wang, L. et al., Science 2011, 333, 765-769; Xu, Y. et al., Nat Commun 2019, 10, 4925). Several TAF1 BRD inhibitors have been reported, with the most potent to date being BAY299 and GNE-371; however, cellular studies are lacking or inconclusive, and no TAF1 inhibitor has yet to reach the clinic (see Foote, K. M. et al., J Med Chem 2018, 61, 9889- 9907; Bouche, L. et al., J Med Chem 2017, 60, 4002-4022; Wang, S. et al., J Med Chem 2018, 61, 9301-9315). There is a clear need for the development of compounds that target the activity of TAF1, particularly in view of the potential effect in the treatment of oncological disorders. The present disclosure addresses this as well as other needs. SUMMARY The present disclosure provides compounds that are degraders of TAF1 that are useful in the treatment of medical disorders, such as cancers. The presently disclosed compounds show improved aqueous solubility and metabolic stability. In one aspect, a compound of Formula I is provided as described herein, or a pharmaceutically acceptable salt or derivative thereof. In another aspect, a pharmaceutical composition is provided comprising a compound of Formula I, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient. Attorney Docket No.10110-450WO1 In yet another aspect, a method is provided of treating a cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or derivative thereof. The details of one or more aspects of the disclosure are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the disclosure will be apparent from the description, drawings, and claims. DESCRIPTION OF DRAWINGS FIGs.1A-1D depict representative TAF1 PROTAC designs of the present disclosure. (FIG. 1A) Representative monovalent inhibitors of TAF1 used in degraders of the present disclosure. (FIG.1B) Cereblon E3 ligase ligands used in degraders of the present disclosure. (FIG. 1C) General structures of PROTACs of the present disclosure. (FIG. 1D) Linker and spacer types used in the present disclosure. FIGs. 2A-2C depict representative linker designs for degraders of the present _{disclosure. (FIG. 2A) Linker modifications made to ZS3 025 providing an in vivo active} _{lead (ZS3 046). (FIG. 2B) Additional linker modifications for ZS3 046. (FIG. 2C) Use of a} _{BCB sulfinamide reagent to prepare S(VI) BCB based spacers.} FIGs. 3A-3F show that PROTACs based on AZD6738 and GNE371 are potent degraders of TAF1. (FIG. 3A) Structures of AZD6738-based PROTACs. (FIG. 3B) Structures of GNE371-based PROTACs. (FIG. 3C) AZD6738-based PROTAC depletes TAF1 after short treatment of HL60 AML cells. (FIG. 3D) TAF1 depletion is blocked by monovalent inhibitors of the proteasome, CRBN and TAF1. (FIG. 3E) GNE371-based PROTAC deplete TAF1 at sub-nM concentration upon short treatment of HL60 cells. (FIG. 3F) UC3 cells were treated with ZS3-025 for indicated times, washed 3 times to remove the compound, and cultured for 4-48 hr. TAF1 level was determined by Western blot. FIGs. 4A-4C show that TAF1 PROTACs induce apoptosis in AML and solid tumor cell lines. (FIG. 4A) Morphological changes of AML cells (Kasumi-1, HL60) and osteosarcoma cell line Saos2 treated with TAF1 PROTAC compounds for 24 hr. (FIG. 4B) TAF1 depletion and induction of PARP cleavage in AML cells by GNE371 and AZD6738- based PROTACs after 18 hr treatment. (FIG. 4C) Induction of PARP cleavage and down- regulation of c-Myc by GNE371-based PROTAC in Saos2 osteosarcoma and T47D breast Attorney Docket No.10110-450WO1 cancer cells after 24 hr treatment. Controls were treated with 50 nM GNE371+50 nM Pomalidomide. FIG. 5 shows that TAF1 PROTAC has potent growth inhibition activity against AML cells. AML, bladder cancer cell lines, and non-transformed skin fibroblasts were treated with TAF1 PROTAC ZS3-025 for 96 hr at indicated concentrations. Cell viability was determined by incubation with MTS reagent and measuring OD490. Controls were treated with 1:1 mixture of monovalent TAF1 and CRBN binding warheads at indicated concentrations. FIGs. 6A-6C show that non-degradable TAF1 mutant inhibits apoptosis by GNE371 PROTAC. (FIG. 6A) Saos2 cells stably transfected with HA-TAF1 expression plasmids were treated with GNE371 PROTAC ZS3-025 for 5 hr. Total TAF1 level was determined by Western blot. (FIG. 6B) Saos2 cells stably transfected with HA-TAF1 were treated with ZS3-025 for 7 days, relative cell survival was documented by microscopy. (FIG.6C) Stably transfected Saos2 cells surviving 7 days of ZS3-025 treatment were expanded into cell lines and analyzed for HA-TAF1 level by Western blot in comparison to unchallenged cells. FIGs. 7A-7C show that TAF1 depletion by PROTAC activates p53. (FIG. 7A) Molm13 and MV-4-11 cells with wt p53 were treated with TAF1 PROTACs, MDM2 inhibitor Nutlin, and DNA damaging drug etoposide and analyzed for indicated markers by Western blot. (FIG. 7B) Molm13 cells with p53 knockout by CRISPR/Cas9 editing were treated with ZS3-025 and analyzed for the expression of indicated markers by Western blot. (FIG. 7C) Molm13 cells with and without p53 knockout were treated with ZS3-025 for 96 hr at indicated concentrations. Cell viability was determined by incubation with MTS reagent. FIGs. 8A-8E depict development of TAF1 PROTAC with in vivo activity. (FIG. 8A) Structures GNE371-based PROTACs with ionizable linkers for in vivo formulation. (FIG. 8B) Activity of PROTAC derivatives in cell culture was determined by Western blot after treating Molm13 cells for 18 hr. (FIG. 8C) Mice were treated with a single i.p injection of ZS3-046 at indicated levels and tissues were analyzed by Western blot after 24 hr. (FIG.8D) Mice were treated with a single i.p injection of ZS3-046 at 40 mg/kg and tissues were analyzed for TAF1 level at indicated times after injection. (FIG. 8E) Mice with subcutaneous HL60 tumors (~600-800 mg) were treated with a single i.p injection of ZS3- 046 at 40 mg/kg. Tumors were collected after 24 hr and analyzed with TAF1 Western blot. Attorney Docket No.10110-450WO1 FIGs. 9A-9D depict the effect of TAF1 PROTAC treatment on mRNA and protein expression. (FIG. 9A) Volcano plot of differential gene expression between Molm13 cells treated for 8 hours with 100 nM ZS3-046 and DMSO control. The mRNA levels of 4380 genes (23% of 18800 gene transcriptome) were altered. Blue:1590 genes (8.5% of transcriptome) were down-regulated by 2-16 fold. Red: 2790 genes (15% of transcriptome) were induced by 2-64 fold. (FIG. 9B) HL60 cells were treated with 100 nM ZS3-046 and control ZS3-061 for 6 hours. TAF1 depletion was confirmed by western blot. Triplicate samples were subjected to tandem mass tag analysis. (FIG. 9C) Volcano plots of protein level changes after PROTAC treatment compared to ZS3-061 control. (FIG. 9D) Top decreased proteins after ZS3-046 treatment. Highlighted protein (MIER1) meets the cutoff after normalization: protein log2Foldchange-mRNA log2Foldchange<-1. FIGs. 10A-10D depict the in vivo toxicity and therapeutic activity of TAF1 PROTAC. (FIG. 10A) C57BL/6 mice were treated with different levels of ZS3-046 at indicated intervals by i.p injections and monitored for weight change and signs of toxicity. Each line represents a single animal. Animals with responses meeting endpoint criteria were euthanized (40 mg/kg, 20 mg/kg). (FIG. 10B) Histology report of animal treated with 6 injections of ZS3-046 at 20 mg/kg. (FIG. 10C) Nude mice with subcutaneous HL60 tumors were treated with 5 mg/kg and 10 mg/kg of ZS3-046 or vehicle at indicated time points (arrows). Average tumor weight of each cohort was plotted. Error bars represent standard deviation. p value was based on day-9 measurements. (FIG. 10D) Average body weight of mice treated with ZS3-046 at indicated doses and times. Error bars represent standard deviation. FIGs. 11A-11C depict the effects of TAF1 PROTAC on cell cycle profile. Representative cell lines treated with TAF1 PROTAC ZS3-025 for 72 hr were stained with propidium iodide and analyzed by FACS for cell cycle distribution. Controls were treated with 1:1 mixture of monovalent TAF1 and CRBN binding warheads. Cells with 4N (G2/M phase), 2N (G1 phase), and sub-2N DNA content were indicated. The size of sub-2N population indicate strong apoptosis (FIG. 11A), modest apoptosis (FIG. 11B), no apoptosis (FIG.11C). FIGs. 12A-12B show that AZD6738 PROTAC induces apoptosis independent of TAF1 degradation. (FIG. 12A) HL60 cells were treated with AZD6738 PROTAC ZS1-958 and monovalent competitors for 24 hr and analyzed for indicated markers by Western blot. (FIG. 12B) HL60 cells were treated with AZD6738 PROTAC ZS1-958, GNE371 PROTAC Attorney Docket No.10110-450WO1 ZS3-025 and monovalent GNE371 for 24 hr and analyzed for indicated markers by Western blot. DETAILED DESCRIPTION The following description of the disclosure is provided as an enabling teaching of the disclosure in its best, currently known aspects. Many modifications and other aspects disclosed herein will come to mind to one skilled in the art to which the disclosed compositions and methods pertain, having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the disclosures are not to be limited to the specific aspects disclosed and that modifications and other aspects are intended to be included within the scope of the appended claims. The skilled artisan will recognize many variants and adaptations of the aspects described herein. These variants and adaptations are intended to be included in the teachings of this disclosure and to be encompassed by the claims herein. Although specific terms are employed herein, they are used in a generic and ^{descriptive sense only and not for purposes of limitation.} As can be apparent to those of skill in the art upon reading this disclosure, each of the individual aspects described and illustrated herein has discrete components and features that may be readily separated from or combined with the features of any of the other several aspects without departing from the scope or spirit of the present disclosure. Any recited method can be carried out in the order of events recited or in any other order that is logically possible. That is, unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred in any respect. This holds for any possible non- express basis for interpretation, including matters of logic with respect to the arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited. The publications discussed herein are provided solely for their disclosure prior to the Attorney Docket No.10110-450WO1 filing date of the present application. Further, the dates of publication provided herein can be different from the actual publication dates, which can require independent confirmation. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosed compositions and methods belong. It can be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly defined herein. Prior to describing the various aspects of the present disclosure, the following definitions are provided and should be used unless otherwise indicated. Additional terms may be defined elsewhere in the present disclosure. Definitions As used herein, “comprising” is to be interpreted as specifying the presence of the stated features, integers, steps, or components as referred to but does not preclude the presence or addition of one or more features, integers, steps, or components, or groups thereof. Moreover, each of the terms “by,” “comprising,” “comprises,” “comprised of,” “including,” “includes,” “included,” “involving,” “involves,” “involved,” and “such as” are used in their open, non-limiting sense and may be used interchangeably. Further, the term “comprising” is intended to include examples and aspects encompassed by the terms “consisting essentially of” and “consisting of.” Similarly, the term “consisting essentially of” is intended to include examples encompassed by the term “consisting of. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a compound,” “a composition,” or “a cancer” includes, but is not limited to, two or more such compounds, compositions, or cancers, and the like. It should be noted that ratios, concentrations, amounts, and other numerical data can be expressed herein in a range format. It can be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint and independently of the other endpoint. It is also understood that there are a number of values disclosed herein and that each value is also herein disclosed as “about” that particular value in addition to the Attorney Docket No.10110-450WO1 value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. Ranges can be expressed herein as from “about” one particular value and/or to “about” another particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it can be understood that the particular value forms a further aspect. For example, if the value “about 10” is disclosed, then “10” is also disclosed. When a range is expressed, a further aspect includes from the one particular value and/or to the other particular value. For example, where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure, e.g., the phrase “x to y” includes the range from ‘x’ to ‘y’ as well as the range greater than ‘x’ and less than ‘y’. The range can also be expressed as an upper limit, e.g., ‘about x, y, z, or less’ and should be interpreted to include the specific ranges of ‘about x,’ ‘about y’, and ‘about z’ as well as the ranges of ‘less than x,’ less than y’, and ‘less than z’. Likewise, the phrase ‘about x, y, z, or greater’ should be interpreted to include the specific ranges of ‘about x,’ ‘about y’, and ‘about z’ as well as the ranges of ‘greater than x,’ greater than y’, and ‘greater than z.’ In addition, the phrase “about ‘x’ to ‘y’,” where ‘x’ and ‘y’ are numerical values, includes “about ‘x’ to about ‘y’.” It is to be understood that such a range format is used for convenience and brevity and, thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range but also all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub- range is explicitly recited. To illustrate, a numerical range of “about 0.1% to 5%” should be interpreted to include not only the explicitly recited values of about 0.1% to about 5% but also include individual values (e.g., about 1%, about 2%, about 3%, and about 4%) and the sub-ranges (e.g., about 0.5% to about 1.1%; about 5% to about 2.4%; about 0.5% to about 3.2%, and about 0.5% to about 4.4%, and other possible sub-ranges) within the indicated range. As used herein, the terms “about,” “approximate,” “at or about,” and “substantially” mean that the amount or value in question can be the exact value or a value that provides equivalent results or effects as recited in the claims or taught herein. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact but may be approximate and/or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art such that equivalent results or effects are Attorney Docket No.10110-450WO1 obtained. In some circumstances, the value that provides equivalent results or effects cannot be reasonably determined. In such cases, it is generally understood, as used herein, that “about” and “at or about” mean the nominal value indicated ±10% variation unless otherwise indicated or inferred. In general, an amount, size, formulation, parameter, or other quantity or characteristic is “about,” “approximate,” or “at or about,” whether or not expressly stated to be such. It is understood that where “about,” “approximate,” or “at or about” is used before a quantitative value, the parameter also includes the specific quantitative value itself unless specifically stated otherwise. As used herein, the term “therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms but is generally insufficient to cause adverse side effects. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts. In the case of treating a particular disease or condition, in some instances, the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease. The desired response to treatment of the disease or condition can also be delaying the onset or even preventing the onset of the disease or condition. For example, it is well within the skill of the art to start doses of a compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. If desired, the effective daily dose can be divided into multiple doses for administration purposes. Consequently, single-dose compositions can contain such amounts or submultiples thereof to make up the daily dose. The dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents of the disclosure (alone or in combination with other therapeutic agents) be used, that Attorney Docket No.10110-450WO1 is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons, or virtually any other reasons. A response to a therapeutically effective dose of a disclosed compound or composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following the administration of the treatment or pharmacological agent. Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response. The amount of a treatment may be varied, for example, by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, changing the disclosed compound and/or pharmaceutical composition administered, changing the route of administration, changing the dosage timing, and so on. Dosage can vary and can be administered in one or more doses daily for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products. As used herein, the terms “optional” or “optionally” mean that the subsequently described event or circumstance can or cannot occur and that the description includes instances where said event or circumstance occurs and instances where it does not. As used interchangeably herein, “subject,” “individual,” or “patient” can refer to a vertebrate organism, such as a mammal (e.g., human). "Subject" can also refer to a cell, a population of cells, a tissue, an organ, or an organism, preferably to a human and constituents thereof. As used herein, the terms "treating" and "treatment" can refer generally to obtaining a desired pharmacological and/or physiological effect. The effect can be but does not necessarily have to be, prophylactic in terms of preventing or partially preventing a disease, symptom, or condition thereof, such as an oncological disorder. The effect can be therapeutic in terms of a partial or complete cure of a disease, condition, symptom, or adverse effect attributed to the disease, disorder, or condition. The term "treatment" as used herein can include any treatment of a disorder in a subject, particularly a human, and can include any one or more of the following: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., mitigating or ameliorating the disease and/or its symptoms or conditions. The term Attorney Docket No.10110-450WO1 "treatment," as used herein, can refer to both therapeutic treatment alone, prophylactic treatment alone, or both therapeutic and prophylactic treatment. Those in need of treatment (subjects in need thereof) can include those already with the disorder and/or those in which the disorder is to be prevented. As used herein, the term "treating" can include inhibiting the disease, disorder, or condition, e.g., impeding its progress, and relieving the disease, disorder, or condition, e.g., causing regression of the disease, disorder, and/or condition. Treating the disease, disorder, or condition can include ameliorating at least one symptom of the particular disease, disorder, or condition, even if the underlying pathophysiology is not affected, e.g., such as treating the pain of a subject by administration of an analgesic agent even though such agent does not treat the cause of the pain. As used herein, “dose,” “unit dose,” or “dosage” can refer to physically discrete units suitable for use in a subject, each unit containing a predetermined quantity of a disclosed compound and/or a pharmaceutical composition thereof calculated to produce the desired response or responses in association with its administration. As used herein, “therapeutic” can refer to treating, healing, and/or ameliorating a disease, disorder, condition, or side effect or to decreasing the rate of advancement of a disease, disorder, condition, or side effect. Chemical Definitions Compounds are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. The compounds described herein include enantiomers, mixtures of enantiomers, diastereomers, tautomers, racemates, and other isomers, such as rotamers, as if each is specifically described, unless otherwise indicated or otherwise excluded by context. It is to be understood that the compounds provided herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration. The compounds provided herein may either be enantiomerically pure or be diastereomeric or enantiomeric mixtures. It is to be understood that the chiral centers of the compounds provided herein may undergo epimerization in vivo. As such, one of skill in the art will recognize that administration of a compound in its (R) form is equivalent, for compounds that undergo epimerization in vivo, to the administration of the compound in its (S) form. Unless stated to the contrary, a formula with chemical bonds shown only as solid lines and not as wedges or dashed lines Attorney Docket No.10110-450WO1 contemplates each possible isomer, e.g., each enantiomer, diastereomer, and meso compound, and a mixture of isomers, such as a racemic or scalemic mixture. Compounds described herein may contain one or more double bonds and, thus, potentially give rise to cis/trans (E/Z) isomers, as well as other conformational isomers. Unless states to the contrary, all such possible isomers are contemplated, as well as mixtures of such isomers. Compounds described herein may also present as an equilibrium of tautomers. For example, ketones with an -hydrogen can exist in an equilibrium of the keto form and the enol form. Likewise, amides with an N-hydrogen can exist in an equilibrium of the amide form and the imidic acid form. Unless stated to the contrary, all possible tautomers of the compounds described herein are contemplated. A dash

that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -(C=O)NH2 is attached through the carbon of the keto (C=O) group. The term “substituted,” as used herein, means that any one or more hydrogens on the designated atom or group are replaced with a moiety selected from the indicated group, provided that the designated atom’s normal valence is not exceeded and the resulting compound is stable. For example, when the substituent is oxo (i.e., =O), two hydrogens on the atom are replaced. For example, a pyridyl group substituted by oxo is a pyridine. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable active compound refers to a compound that can be isolated and can be formulated into a dosage form with a shelf life of at least one month. A stable manufacturing intermediate or precursor to an active compound is stable if it does not degrade within the period needed for reaction or other use. A stable moiety or substituent group is one that does not degrade, react, or fall apart within the period necessary for use. Non-limiting examples of unstable moieties are those that combine heteroatoms in an unstable arrangement, as typically known and identifiable to those of skill in the art. Any suitable group may be present on a “substituted” or “optionally substituted” position that forms a stable molecule and meets the desired purpose of the disclosure and includes, but is not limited to: halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered Attorney Docket No.10110-450WO1 monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-, A^xO-(C0-C6 alkyl)-, A^xS-(C0-C6 alkyl)-, (A^xA^yN)-(C0-C6 alkyl)-, A^zC(O)-(C0-C6 alkyl)-, A^zC(N)-(C0-C6 alkyl)-, and A^zS(O)-(C0-C6 alkyl)-, and A^zS(O)2-(C0-C6 alkyl)-, wherein A^x and A^y are independently selected at each occurrence from A^a, A^zC(O)-, A^zC(N)- , A^zS(O)-, and A^zS(O)2-, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein A^z is independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)- (C0-C3 alkyl)-, (4- to 6-membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OA^a, -SA^a, and -NA^aA^b, each of which may be optionally substituted with one or more B groups as allowed by valency; wherein A^a and A^b are independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2- C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6-membered heterocycle)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted by one or more B groups as allowed by valency; and wherein B is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)- , (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10- membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-,

, A^pS-, A^pA^qN-, A^oC(O)-, A^oC(O)-O-, A^oC(O)-NA^q- , A^oS(O)2-, A^oS(O)2-O-, and A^oS(O)2-NA^q-, wherein A^o is independently selected at each occurrence from A^p, halo, A^pO-, and A^pA^qN-, and wherein A^p and A^q are independently selected at each occurrence from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2- C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C6 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C6 alkyl)-, and (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C6 alkyl)-. The terms for various functional groups as used herein are not intended to be limited to monovalent radicals and may include polyvalent radical groups as appropriate, such as divalent, trivalent, tetravalent, pentavalent, and hexavalent groups, and the like, based on the position and location of such groups in the compounds described herein as would be readily understood by the skilled person. Attorney Docket No.10110-450WO1 A_{s used herein, the symbol}

_{” (which hereinafter can be referred to as “a} point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of which is not depicted as being attached to the point of attachment bond. For _{example, “ ” indicates that the chemical entity “XY” is bonded to another chemical} entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound _{CH3-R3, wherein R3 is H or “ ” infers that when R3 is “XY”, the point of} attachment bond is the same bond as the bond by which R³ is depicted as being bonded to CH3. “Halo” or “halogen” indicates, independently, any of fluoro, chloro, bromo or iodo. The term “nitro” as used herein is represented by the formula —NO2. The term “cyano” as used herein is represented by the formula —CN The term “azido” as used herein is represented by the formula –N3. The term “oxo” as used herein is represented by the formula =O. “Alkyl” is a straight chain or branched saturated aliphatic hydrocarbon group. In certain aspects, the alkyl is C1-C2, C1-C3, or C1-C6 (i.e., the alkyl chain can be 1, 2, 3, 4, 5, or 6 carbons in length). The specified ranges, as used herein, indicate an alkyl group with a length of each member of the range described as an independent species. For example, C1- C6alkyl, as used herein, indicates an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms and is intended to mean that each of these is described as an independent species, and C1- C4alkyl, as used herein, indicates an alkyl group having from 1, 2, 3, or 4 carbon atoms and is intended to mean that each of these is described as an independent species. When C0- Cnalkyl is used herein in conjunction with another group, for example (C3-C7cycloalkyl)C0- C4alkyl, or -C0-C4(C3-C7cycloalkyl), the indicated group, in this case cycloalkyl, is either directly bound by a single covalent bond (C0alkyl), or attached by an alkyl chain, in this case 1, 2, 3, or 4 carbon atoms. Alkyls can also be attached via other groups, such as heteroatoms, as in -O-C0-C4alkyl(C3-C7cycloalkyl). Examples of alkyl include but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, tert-pentyl, neopentyl, n-hexyl, 2-methylpentane, 3-methylpentane, 2,2- Attorney Docket No.10110-450WO1 dimethylbutane, and 2,3-dimethylbutane. In one aspect, the alkyl group is optionally substituted as described herein. “Cycloalkyl” is a saturated mono- or multi-cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused or bridged fashion. Non-limiting examples of typical cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In one aspect, the cycloalkyl group is optionally substituted as described herein. “Alkenyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon double bonds, each of which is independently either cis or trans, that may occur at a stable point along the chain. Non-limiting examples include C2-C4alkenyl and C2-C6alkenyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkenyl group having each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkenyl include but are not limited to, ethenyl and propenyl. In one aspect, the alkenyl group is optionally substituted as described herein. “Alkynyl” is a straight or branched chain aliphatic hydrocarbon group having one or more carbon-carbon triple bonds that may occur at any stable point along the chain, for example, C2-C4alkynyl or C2-C6alkynyl (i.e., having 2, 3, 4, 5, or 6 carbons). The specified ranges as used herein indicate an alkynyl group, with each member of the range described as an independent species, as described above for the alkyl moiety. Examples of alkynyl include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1- pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexynyl. In one aspect, the alkynyl group is optionally substituted as described herein. “Alkoxy” is an alkyl group, as defined above, covalently bound through an oxygen bridge (-O-). Examples of alkoxy include but are not limited to, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, 2-butoxy, tert-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Similarly, an “alkylthio” or “thioalkyl” group is an alkyl group, as defined above, with the indicated number of carbon atoms covalently bound through a sulfur bridge (-S-). In one aspect, the alkoxy group is optionally substituted as described herein. Attorney Docket No.10110-450WO1 “Alkanoyl” is an alkyl group, as defined above, covalently bound through a carbonyl (C=O) bridge. The carbonyl carbon is included in the number of carbons. For example, C2alkanoyl is a CH3(C=O)- group. In one aspect, the alkanoyl group is optionally substituted as described herein. “Aryl” indicates an aromatic group containing only carbon in the aromatic ring or rings. In one aspect, the aryl group contains 1 to 3 separate or fused rings and is 6 to 14 or 18 ring atoms, without heteroatoms as ring members. When indicated, such aryl groups may be further substituted with carbon or non-carbon atoms or groups. Such substitution may include fusion to a 4- to 7- or 5- to 7-membered saturated or partially unsaturated cyclic group that optionally contains 1, 2, or 3 heteroatoms independently selected from N, O, B, P, Si, and S to form, for example, a 3,4-methylenedioxyphenyl group. Aryl groups include, for example, phenyl and naphthyl, including 1-naphthyl and 2-naphthyl. In one aspect, aryl groups are pendant. An example of a pendant ring is a phenyl group substituted with a phenyl group. In one aspect, the aryl group is optionally substituted as described herein. The term “heterocycle” refers to saturated and partially saturated heteroatom- containing ring radicals, where the heteroatoms may be selected from N, O, and S. The term heterocycle includes monocyclic 3-12 members rings, as well as bicyclic 5-16 membered ring systems (which can include fused, bridged, or spiro bicyclic ring systems). It does not include rings containing -O-O-, -O-S-, and -S-S- portions. Examples of saturated heterocycle groups including saturated 4- to 7-membered monocyclic groups containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, azetidinyl, piperazinyl, and pyrazolidinyl]; saturated 4- to 6-membered monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., morpholinyl]; and saturated 3- to 6- membered heteromonocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., thiazolidinyl]. Examples of partially saturated heterocycle radicals include, but are not limited to, dihydrothienyl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Examples of partially saturated and saturated heterocycle groups include, but are not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, thiazolidinyl, dihydrothienyl, 2,3-dihydro- benzo[1,4]dioxanyl, indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl, isochromanyl, chromanyl, 1,2-dihydroquinolyl, 1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4- tetrahydro-quinolyl, 2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl, 5,6,7-trihydro-1,2,4- triazolo[3,4-a]isoquinolyl, 3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl, 2,3,- Attorney Docket No.10110-450WO1 dihydro-1H-benzo[d]isothazol-6-yl, dihydropyranyl, dihydrofuryl, and dihydrothiazolyl. Bicyclic heterocycle includes groups wherein the heterocyclic radical is fused with an aryl radical wherein the point of attachment is the heterocycle ring. Bicyclic heterocycle also includes heterocyclic radicals that are fused with a carbocyclic radical. Representative examples include but are not limited to, partially unsaturated condensed heterocyclic groups containing 1 to 5 nitrogen atoms, for example, indoline and isoindoline, partially unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, partially unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, and saturated condensed heterocyclic groups containing 1 to 2 oxygen or sulfur atoms. “Heteroaryl” refers to a stable monocyclic, bicyclic, or multicyclic aromatic ring that contains from 1 to 4, or in some aspects 1, 2, or 3 heteroatoms selected from N, O, S, B, and P (and typically selected from N, O, and S) with remaining ring atoms being carbon, or a stable bicyclic or tricyclic system containing at least one 5, 6, or 7 membered aromatic ring which contains from 1 to 4, or in some aspects from 1 to 3 or from 1 to 2, heteroatoms selected from N, O, S, B, or P, with remaining ring atoms being carbon. In one aspect, the only heteroatom is nitrogen. In one aspect, the only heteroatom is oxygen. In one aspect, the only heteroatom is sulfur. Monocyclic heteroaryl groups typically have 5- 6 ring atoms. In some aspects, bicyclic heteroaryl groups are 8- to 10-membered heteroaryl groups, that is, groups containing 8- or 10-ring atoms in which one 5-, 6-, or 7-membered aromatic ring is fused to a second aromatic or non-aromatic ring, wherein the point of attachment is the aromatic ring. When the total number of S and O atoms in the heteroaryl group excess 1, these heteroatoms are not adjacent to one another. In one aspect, the total number of S and O atoms in the heteroaryl group is not more than 2. In another aspect, the total number of S and O atoms in the heteroaryl group is not more than 1. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridinyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, furyl, thienyl, isoxazolyl, thiazolyl, oxadiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Attorney Docket No.10110-450WO1 A “pharmaceutically acceptable salt” is a derivative of the disclosed compound in which the parent compound is modified by making inorganic and organic, pharmaceutically acceptable, acid or base addition salts thereof. The salts of the present compounds can be synthesized from a parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like) or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water, in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are typical, where practicable. Salts of the present compounds further include solvates of the compounds and of the compound salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include salts that are acceptable for human consumption and the quaternary ammonium salts of the parent compound formed, for example, from inorganic or organic salts. Example of such salts include, but are not limited to, those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicyclic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC-(CH2)1-4-COOH, and the like, or using a different acid that produced the same counterion. Lists of additional suitable salts may be found, e.g., in Remington’s Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, PA., p. 1418 (1985). As used herein, the term “derivative” refers to a compound having a structure derived from the structure of a parent compound (e.g., a compound disclosed herein) and whose structure is sufficiently similar to those disclosed herein and based upon that similarity would be expected by one skilled in the art to exhibit the same or similar activities and utilities as the claimed compounds, or to induce, as a precursor, the same or similar activities and utilities as the claimed compound. Exemplary derivatives include but Attorney Docket No.10110-450WO1 are not limited to, salts, esters, amides, salts of esters or amides, and N-oxides of a parent compound. As used herein, substantially pure means sufficiently homogeneous to appear free of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC), nuclear magnetic resonance (NMR), gel electrophoresis, high-performance liquid chromatography (HPLC) and mass spectrometry (MS), gas- chromatography mass spectrometry (GC-MS), and similar, used by those of skill in the art to assess such purity, or sufficiently pure such that further purification would not detectably alter the physical and chemical properties, such as enzymatic and biological activities, of the substance. Both traditional and modern methods for purification of the compounds to produce substantially chemically pure compounds are known to those skilled in the art. A substantially chemically pure compound may, however, be a mixture of stereoisomers. Certain materials, compounds, compositions, and components disclosed herein can be obtained commercially or readily synthesized using techniques generally known to those of skill in the art. For example, the starting materials and reagents used in preparing the disclosed compounds and compositions are either available from commercial suppliers, such as Sigma-Aldrich (formally MilliporeSigma, Burlington, MA) or Thermo Fisher Scientific Inc. (Waltham, MA), or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis (John Wiley and Sons, 2007); Organic Reactions (John Wiley and Sons, 2004); March's Advanced Organic Chemistry, (John Wiley and Sons, 8^th Edition); and Larock's Comprehensive Organic Transformations (John Wiley and Sons, 3^rd edition, 2017). Compounds The present disclosure provides compounds capable of the targeted degradation of the protein TAF1. The presently disclosed compounds are useful in the treatment of medical disorders, in particular cancers. In one aspect, a compound is provided of Formula I A-L-B (I) or a pharmaceutically acceptable salt or derivative thereof; wherein: Attorney Docket No.10110-450WO1 A is

a double bond; B is an E3 ubiquitin ligase-recruiting moiety; L is selected from

, -L¹-Q¹-L²-, -L¹-Q²-L²-Q³-, -L¹-Q⁴-L²-, and -Q⁵-L¹-Q⁶-; m1 is 1, 2, 3, 4, or 5; L¹ and L² are independently selected from C1-C6 alkyl and

; m2 is 1, 2, or 3; Q¹, Q³, Q⁵, and Q⁶ are independently selected from 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more groups selected from Z as allowed by valency; Q² is selected from 3- to 8-membered monocyclic or bicyclic heterocycle, 5- to 10- membered monocyclic or bicyclic heteroaryl, and C3-C9 monocyclic or bicyclic cycloalkyl, each of which may be optionally substituted with one or more groups selected from Z as allowed by valency;

X¹ is selected from -N(R^x)-, -O-, -S-, and 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more groups selected from Z; Y¹ is selected from O and NH; X² is absent or -N(R^x)-; Attorney Docket No.10110-450WO1 Z is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, R^xO-(C0-C3 alkyl)-, R^xS-(C0- C3 alkyl)-, (R^xR^yN)-(C0-C3 alkyl)-, R^xO-C(O)-(C0-C3 alkyl)-, R^xS-C(O)-(C0-C3 alkyl)-, (R^xR^yN) C(O)-(C0-C3 alkyl)-, R^xO-S(O)2-(C0-C3 alkyl)-, (R^xR^yN) S(O)2-(C0-C3 alkyl)-, R^zC(O)-O-(C0-C3 alkyl)-, R^zC(O)-(R^xN)-(C0-C3 alkyl)-, R^zS(O)2-O-(C0-C3 alkyl)-, R^zS(O)2- (R^xN)-(C0-C3 alkyl)-, R^zC(O)-(C0-C6 alkyl)-, R^zS(O)-(C0-C3 alkyl)-, and R^zS(O)2-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency; R^x and R^y are independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; R^z is independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OR^x, -SR^x, and -NR^xR^y, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. In some aspects, the compound of Formula I is selected from: Attorney Docket No.10110-450WO1

In some aspects of Formula I, L is

. In some aspects of Formula I, m1 is 1. In some aspects of Formula I, m1 is 2. In some aspects of Formula I, m1 is 3. In some aspects of Formula I, m1 is 4. In some aspects of Formula I, m1 is 5. In some aspects of Formula I, L is -L¹-Q¹-L²-. In some aspects of Formula I, Q¹ is selected from

, Attorney Docket No.10110-450WO1

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, Q¹ is selected from:

In some aspects of Formula I, L¹ is C1-C6 alkyl. In some aspects of Formula I, L¹ is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. In some aspects of Formula I, L¹ is

. In some aspects of Formula I, L¹ is selected from:

In some aspects of Formula I, L² is C1-C6 alkyl. In some aspects of Formula I, L² is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, and n-hexyl. In some aspects of Formula I, L² is

. In some aspects of Formula I, L² is selected from:

In some aspects of Formula I, L is -L¹-Q²-L²-Q³-. Attorney Docket No.10110-450WO1 In some aspects of Formula I, Q² is 3- to 8-membered monocyclic or bicyclic heterocycle. In some aspects of Formula I, Q² is C3-C9 monocyclic or bicyclic cycloalkyl. In some aspects of Formula I, Q² is selected from

,

wherein X³ and X⁴ are independently selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, Q² is selected from:

In some aspects of Formula I, Q² is 5- to 10-membered monocyclic or bicyclic heteroaryl. In some aspects of Formula I, Q² is

. In some aspects of Formula I, Q³ is selected from

, Attorney Docket No.10110-450WO1

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, Q³ is selected from:

In some aspects of Formula I, X¹ is selected from -NH-, -O-, -

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, X¹ is selected from -NH-, -O-, -S-, Attorney Docket No.10110-450WO1

In some aspects of Formula I, Y¹ is O. In some aspects of Formula I, Y¹ is NH. In some aspects of Formula I, X² is absent. In some aspects of Formula I, X² is NH. In some aspects of Formula I, L is -Q⁵-L¹-Q⁶-.

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, Q⁵ is selected from:

In some aspects of Formula I, Q⁶ is selected from

, Attorney Docket No.10110-450WO1

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. In some aspects of Formula I, Q⁶ is selected from:

The E3 ubiquitin ligase-recruiting moiety B is a chemical moiety capable of recruiting an E3 ubiquitin ligase to a given substrate protein (for example, TAF1) resulting in its targeted degradation. In some aspects, B is a chemical moiety based upon a high affinity small molecule for E3 ubiquitin ligases, such as von Hippel-Lindau or cereblon. In some aspects, B is a chemical moiety based upon a von Hippel-Lindau binder such as VH032 or VH298. In some aspects, B is a chemical moiety based upon a cereblon binder such as thalidomide, lenalidomide, or pomalidomide. In some aspects of Formula I, B is selected from

wherein Z⁵ is selected from O, N(R^x), and CH2. In some aspects of Formula I, B is selected from Attorney Docket No.10110-450WO1

. In some aspects of Formula I, B is selected from

_. In some aspects of Formula I, B is selected from

Attorney Docket No.10110-450WO1 5

In some aspects of Formula I, B is selected from: Attorney Docket No.10110-450WO1

wherein: X⁵ is a bond or selected from -NH-, -O-, and -CH2-; R¹ is hydrogen or -CH2-O-C(=O)-O-(C1-C6 alkyl); X⁶ is selected from CH and N; R² is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and X⁷ is selected from O and NH. The present disclosure also includes compounds described herein with at least one desired isotopic substitution of an atom at an amount above the natural abundance of the isotope, i.e., enriched. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F, ³¹P^{, 32}P, ³⁵S, ³⁶Cl, and ¹²⁵I, respectively. In one aspect, isotopically labeled compounds can be used in metabolic studies (with ¹⁴C), reaction kinetic studies (with, for example, ²H or ³H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug and substrate tissue distribution assays, or in radioactive treatment of patients. In particular, an ¹⁸F-labeled compound may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed herein by substituting a readily available isotopically labeled reagent for a non- isotopically labeled reagent. By way of general example and without limitation, isotopes of hydrogen, for example, deuterium (²H) and tritium (³H), may optionally be used anywhere in described structures that achieve the desired result. Alternatively, or in addition, isotopes of carbon, e.g., ¹³C and ¹⁴C, may be used. In one aspect, the isotopic substitution is replacing hydrogen with deuterium at one or more locations on the molecule to improve the performance of the Attorney Docket No.10110-450WO1 molecule as a drug, for example, the pharmacodynamics, pharmacokinetics, biodistribution, half-life, stability, AUC, Tmax, Cmax, etc. For example, the deuterium can be bound to carbon in the allocation of bond breakage during metabolism (an alpha-deuterium kinetic isotope effect) or next to or near the site of bond breakage (a beta-deuterium kinetic isotope effect). Isotopic substitutions, such as deuterium substitutions, can be partial or complete. Partial deuterium substitution means that at least one hydrogen is substituted with deuterium. In certain aspects, the isotope is 80, 85, 90, 95, or 99% or more enriched in an isotope at any location of interest. In some aspects, deuterium is 80, 85, 90, 95, or 99% enriched at a desired location. Unless otherwise stated, the enrichment at any point is above natural abundance and, in an aspect, is enough to alter a detectable property of the compounds as a drug in a human. The compounds of the present disclosure may form a solvate with solvents (including water). Therefore, in one aspect, the disclosure includes a solvated form of the active compound. The term “solvate” refers to a molecular complex of a compound of the present disclosure (including a salt thereof) with one or more solvent molecules. Non- limiting examples of solvents are water, ethanol, dimethyl sulfoxide, acetone, and other common organic solvents. The term “hydrate” refers to a molecular complex comprising a disclosed compound and water. Pharmaceutically acceptable solvates in accordance with the disclosure include those wherein the solvent of crystallization may be isotopically substituted, e.g., D2O, d6-acetone, or d6-DMSO. A solvate can be in a liquid or solid form. A “prodrug,” as used herein, means a compound that, when administered to a host in vivo, is converted into a parent drug. As used herein, the term “parent drug” means any of the presently described compounds herein. Prodrugs can be used to achieve any desired effect, including to enhance the properties of the parent drug or to improve the pharmaceutic or pharmacokinetic properties of the parent, including increasing the half-life of the drug in vivo. Prodrug strategies provide choices in modulating the conditions for in vivo generation of the parent drug. Non-limiting examples of prodrug strategies include covalent attachment of removable groups or removable portions of groups, for example, but not limited to, acylating, phosphorylation, phosphonylation, phosphoramidate derivatives, amidation, reduction, oxidation, esterification, alkylation, other carboxy derivatives, sulfoxy or sulfone derivatives, carbonylation, or anhydrides, among others. In certain aspects, the prodrug renders the parent compound more lipophilic. In certain aspects, a prodrug can be provided that has several prodrug moieties in a linear, branched, or cyclic manner. For example, non- Attorney Docket No.10110-450WO1 limiting aspects include the use of a divalent linker moiety such as a dicarboxylic acid, amino acid, diamine, hydroxycarboxylic acid, hydroxyamine, di-hydroxy compound, or other compound that has at least two functional groups that can link the parent compound with another prodrug moiety and are typically biodegradable in vivo. In some aspects, 2, 3, 4, or 5 prodrug biodegradable moieties are covalently bound in a sequence, branched, or cyclic fashion to the parent compound. Non-limiting examples of prodrugs according to the present disclosure are formed with: a carboxylic acid on the parent drug and a hydroxylated prodrug moiety to form an ester; a carboxylic acid on the parent drug and an amine prodrug to form an amide; an amino on the parent drug and a carboxylic acid prodrug moiety to form an amide; an amino on the parent drug and a sulfonic acid to form a sulfonamide; a sulfonic acid on the parent drug and an amino on the prodrug moiety to form a sulfonamide; a hydroxyl group on the parent drug and a carboxylic acid on the prodrug moiety to form an ester; a hydroxyl on the parent drug and a hydroxylated prodrug moiety to form an ester; a phosphonate on the parent drug and a hydroxylated prodrug moiety to form a phosphonate ester; a phosphoric acid on the parent drug and a hydroxylated prodrug moiety to form a phosphate ester; a hydroxyl on the parent drug and a phosphonate on the prodrug to form a phosphonate ester; a hydroxyl on the parent drug and a phosphoric acid prodrug moiety to form a phosphate ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ester; a carboxylic acid on the parent drug and a prodrug of the structure HO-(CH2)2-S-(C2-24 alkyl) to form a thioester; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an ether; a hydroxyl on the parent drug and a prodrug of the structure HO-(CH2)2-O-(C2-24 alkyl) to form an thioether; and a carboxylic acid, oxime, hydrazide, hydrazine, amine or hydroxyl on the parent compound and a prodrug moiety that is a biodegradable polymer or oligomer including but not limited to polylactic acid, polylactide-co-glycolide, polyglycolide, polyethylene glycol, polyanhydride, polyester, polyamide, or a peptide. In some aspects, a prodrug is provided by attaching a natural or non-natural amino acid to an appropriate functional moiety on the parent compound, for example, oxygen, nitrogen, or sulfur, and typically oxygen or nitrogen, usually in a manner such that the amino acid is cleaved in vivo to provide the parent drug. The amino acid can be used alone or covalently linked (straight, branched, or cyclic) to one or more other prodrug moieties to modify the parent drug to achieve the desired performance, such as increased half-life, lipophilicity or other drug delivery or pharmacokinetic properties. The amino acid can be Attorney Docket No.10110-450WO1 any compound with an amino group and a carboxylic acid, which includes an aliphatic amino acid, alkyl amino acid, aromatic amino acid, heteroaliphatic amino acid, heteroalkyl amino acid, heterocyclic amino acid, or heteroaryl amino acid. Pharmaceutical Compositions The compounds as used in the methods described herein can be administered by any suitable method and technique presently or prospectively known to those skilled in the art. For example, the active components described herein can be formulated in a physiologically- or pharmaceutically-acceptable form and administered by any suitable route known in the art, including, for example, oral and parenteral routes of administering. As used herein, the term “parenteral” includes subcutaneous, intradermal, intravenous, intramuscular, intraperitoneal, and intrasternal administration, such as by injection. Administration of the active components of their compositions can be a single administration, or at continuous and distinct intervals as can be readily determined by a person skilled in the art. Compositions, as described herein, comprising an active compound and a pharmaceutically acceptable carrier or excipient of some sort may be useful in a variety of medical and non-medical applications. For example, pharmaceutical compositions comprising an active compound and an excipient may be useful for the treatment or prevention of a cancer in a subject in need thereof. "Pharmaceutically acceptable carrier" (sometimes referred to as a "carrier") means a carrier or excipient that is useful in preparing a pharmaceutical or therapeutic composition that is generally safe and non-toxic and includes a carrier that is acceptable for veterinary and/or human pharmaceutical or therapeutic use. The terms "carrier" or "pharmaceutically acceptable carrier" can include, but are not limited to, phosphate-buffered saline solution, water, emulsions (such as an oil/water or water/oil emulsion) and/or various types of wetting agents. As used herein, the term "carrier" encompasses, but is not limited to, any excipient, diluent, filler, salt, buffer, stabilizer, solubilizer, lipid, stabilizer, or other material well-known in the art for use in pharmaceutical formulations and as described further herein. “Excipients” include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the Attorney Docket No.10110-450WO1 particular dosage form desired. General considerations in formulation and/or manufacture can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21st Edition (Lippincott Williams & Wilkins, 2005). Exemplary excipients include, but are not limited to, any non-toxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as excipients include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as Tween 80; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator. As would be appreciated by one of skill in this art, the excipients may be chosen based on what the composition is useful for. For example, with a pharmaceutical composition or cosmetic composition, the choice of the excipient will depend on the route of administration, the agent being delivered, time course of delivery of the agent, etc., and can be administered to humans and/or to animals, orally, rectally, parenterally, intracisternally, intravaginally, intranasally, intraperitoneally, topically (as by powders, creams, ointments, or drops), buccally, or as an oral or nasal spray. In some aspects, the active compounds disclosed herein are administered topically. Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof. Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, Attorney Docket No.10110-450WO1 bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross- linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof. Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl- pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, Attorney Docket No.10110-450WO1 hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof. Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluene (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium Attorney Docket No.10110-450WO1 bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain aspects, the preservative is an anti-oxidant. In other aspects, the preservative is a chelating agent. Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof. Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof. Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, chamomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof. Attorney Docket No.10110-450WO1 Additionally, the composition may further comprise a polymer. Exemplary polymers contemplated herein include, but are not limited to, cellulosic polymers and copolymers, for example, cellulose ethers such as methylcellulose (MC), hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC), methylhydroxyethylcellulose (MHEC), methylhydroxypropylcellulose (MHPC), carboxymethyl cellulose (CMC) and its various salts, including, e.g., the sodium salt, hydroxyethylcarboxymethylcellulose (HECMC) and its various salts, carboxymethylhydroxyethylcellulose (CMHEC) and its various salts, other polysaccharides and polysaccharide derivatives such as starch, dextran, dextran derivatives, chitosan, and alginic acid and its various salts, carageenan, varoius gums, including xanthan gum, guar gum, gum arabic, gum karaya, gum ghatti, konjac and gum tragacanth, glycosaminoglycans and proteoglycans such as hyaluronic acid and its salts, proteins such as gelatin, collagen, albumin, and fibrin, other polymers, for example, polyhydroxyacids such as polylactide, polyglycolide, polyl(lactide-co-glycolide) and poly(.epsilon.-caprolactone-co-glycolide)-, carboxyvinyl polymers and their salts (e.g., carbomer), polyvinylpyrrolidone (PVP), polyacrylic acid and its salts, polyacrylamide, polyacrylic acid/acrylamide copolymer, polyalkylene oxides such as polyethylene oxide, polypropylene oxide, poly(ethylene oxide- propylene oxide), and a Pluronic polymer, polyoxy ethylene (polyethylene glycol), polyanhydrides, polyvinylalchol, polyethyleneamine and polypyrridine, polyethylene glycol (PEG) polymers, such as PEGylated lipids (e.g., PEG-stearate, l,2-Distearoyl-sn-glycero-3- Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-1000], 1,2-Distearoyl-sn-glycero- 3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-2000], and 1,2-Distearoyl-sn- glycero-3-Phosphoethanolamine-N-[Methoxy(Polyethylene glycol)-5000]), copolymers and salts thereof. Additionally, the composition may further comprise an emulsifying agent. Exemplary emulsifying agents include, but are not limited to, a polyethylene glycol (PEG), a polypropylene glycol, a polyvinyl alcohol, a poly-N-vinyl pyrrolidone and copolymers thereof, poloxamer nonionic surfactants, neutral water-soluble polysaccharides (e.g., dextran, Ficoll, celluloses), non-cationic poly(meth)acrylates, non-cationic polyacrylates, such as poly (meth) acrylic acid, and esters amide and hydroxy alkyl amides thereof, natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite [aluminum silicate] and Veegum [magnesium Attorney Docket No.10110-450WO1 aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxy vinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof. In certain aspects, the emulsifying agent is cholesterol. Liquid compositions include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active compound, the liquid composition may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Injectable compositions, such as injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be an injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for Attorney Docket No.10110-450WO1 example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents for pharmaceutical or cosmetic compositions that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any bland fixed oil can be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. In certain aspects, the particles are suspended in a carrier fluid comprising 1% (w/v) sodium carboxymethyl cellulose and 0.1% (v/v) Tween 80. The injectable composition can be sterilized, for example, by filtration through a bacteria-retaining filter or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Compositions for rectal or vaginal administration may be in the form of suppositories which can be prepared by mixing the particles with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the particles. Solid compositions include capsules, tablets, pills, powders, and granules. In such solid compositions, the particles are mixed with at least one excipient and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar- agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they Attorney Docket No.10110-450WO1 release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Compositions for topical or transdermal administration include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active compound is admixed with an excipient and any needed preservatives or buffers as may be required. The ointments, pastes, creams, and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, and zinc oxide, or mixtures thereof. Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the nanoparticles in a proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate- controlling membrane or by dispersing the particles in a polymer matrix or gel. The active ingredient may be administered in such amounts, time, and route deemed necessary in order to achieve the desired result. The exact amount of the active ingredient will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the medical disorder, the particular active ingredient, its mode of administration, its mode of activity, and the like. The active ingredient, whether the active compound itself or the active compound in combination with an agent, is preferably formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the active ingredient will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors, including the disorder being treated and the severity of the disorder; the activity of the active ingredient employed; the specific composition employed; the age, body weight, Attorney Docket No.10110-450WO1 general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. The active ingredient may be administered by any route. In some aspects, the active ingredient is administered via a variety of routes, including oral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, enteral, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. In general, the most appropriate route of administration will depend upon a variety of factors, including the nature of the active ingredient (e.g., its stability in the environment of the gastrointestinal tract), the condition of the subject (e.g., whether the subject is able to tolerate oral administration), etc. The exact amount of an active ingredient required to achieve a therapeutically or prophylactically effective amount will vary from subject to subject, depending on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult. Useful dosages of the active agents and pharmaceutical compositions disclosed herein can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice and other animals to humans are known to the art. The dosage ranges for the administration of the compositions are those large enough to produce the desired effect in which the symptoms or disorder are affected. The dosage should not be so large as to cause adverse side effects, such as unwanted cross-reactions, anaphylactic reactions, and the like. Generally, the dosage will vary with the age, condition, sex, and extent of the disease in the patient and can be determined by one of skill in the art. The dosage can be adjusted by the individual physician in the event of any Attorney Docket No.10110-450WO1 counterindications. Dosage can vary and can be administered in one or more doses daily for one or several days. Methods of Use The present disclosure also provides methods for treating or preventing cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. The methods can further comprise administering one or more additional therapeutic agents, such as anti-cancer agents or anti- inflammatory agents. Additionally, the method can further comprise administering a therapeutically effective amount of ionizing radiation to the subject. Methods of killing a cancer or tumor cell are also provided comprising contacting the cancer or tumor cell with an effective amount of a compound or composition as described herein. In some aspects, the compounds can facilitate degradation of TAF1. The methods can further include administering one or more additional therapeutic agents or administering an effective amount of ionizing radiation. The disclosed methods can optionally include identifying a patient who is or can be in need of treatment of an oncological disorder. The patient can be a human or other mammal, such as a primate (monkey, chimpanzee, ape, etc.), dog, cat, cow, pig, or horse, or other animals having an oncological disorder. In some aspects, the subject can receive the therapeutic compositions prior to, during, or after surgical intervention to remove part or all of a tumor. In some aspects, the cancer to be treated is a TAF1-associated cancer. Thus, a method of treating TAF1-associated cancer in a subject in need thereof is also provided, the method comprising administering to the subject a therapeutically effective amount of a compound or composition described herein. As used herein, a “TAF1-associated cancer” refers to a cancer having a dysregulation of TAF1 via an associated gene, an associated protein, or expression or activity or level of the same. Representative examples of dysregulation of TAF1 include, but are not limited to: overexpression of wildtype TAF1 or overexpression or underexpression of an associated protein, including any proteins downstream or upstream of TAF1 in an associated signaling or regulatory pathway; and insertions, deletions, or other mutations (such as expression of a fusion protein) in TAF1 or other associated protein, including any proteins downstream or upstream of TAF1 in an associated signaling or regulatory pathway. Attorney Docket No.10110-450WO1 In some aspects, an assay can be used to determine whether the subject has dysregulation of TAF1 via an associated gene, an associated protein, or expression or activity, or level of the same, using a sample (e.g., a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from a subject. Representative examples of such assays can include, for example, next-generation sequencing, immunohistochemistry, fluorescence microscopy, break-apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR). As is well- known in the art, the assays are typically performed, e.g., with at least one labeled nucleic acid probe or at least one labeled antibody or antigen-binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of TAF1. The term “neoplasia” or “cancer” is used throughout this disclosure to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue (solid) or cells (non-solid) that grow by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease. Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue, and most invade surrounding tissues, can metastasize to several sites, are likely to recur after attempted removal and may cause the death of the patient unless adequately treated. As used herein, the term neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant, hematogenous, ascitic, and solid tumors. The cancers that may be treated by the compositions disclosed herein may comprise carcinomas, sarcomas, lymphomas, leukemias, germ cell tumors, or blastomas. Carcinomas which may be treated by the compositions of the present disclosure include, but are not limited to, acinar carcinoma, acinous carcinoma, alveolar adenocarcinoma, carcinoma adenomatosum, adenocarcinoma, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellular, basaloid carcinoma, basosquamous cell carcinoma, breast carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid carcinoma, epibulbar carcinoma, epidermoid carcinoma, carcinoma epitheliate adenoids, carcinoma exulcere, carcinoma fibrosum, gelatinform carcinoma, gelatinous carcinoma, Attorney Docket No.10110-450WO1 giant cell carcinoma, gigantocellulare, glandular carcinoma, granulose cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma,hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's _{carcinoma, Kulchitzky cell carcinoma, lentivular carcinoma, carcinoma lenticulare,} lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma mastotoids, carcinoma medullare, medullary carcinoma, carcinoma melanodes, melanotonic carcinoma, mucinous carcinoma, carcinoma muciparum, carcinoma mucocullare, mucoepidermoid carcinoma, mucous carcinoma, carcinoma myxomatodes, masopharyngeal carcinoma, carcinoma nigrum, oat cell carcinoma, carcinoma ossificans, osteroid carcinoma, ovarian carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prostate carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, scheinderian _{carcinoma, scirrhous carcinoma, carcinoma scrota, signet ring cell carcinoma, carcinoma} simplex, small cell carcinoma, solandoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberrosum, tuberous carcinoma, verrucous carcinoma, and carcinoma vilosum. Representative sarcomas which may be treated by the compositions of the present disclosure include, but are not limited to, liposarcomas (including myxoid liposarcomas and pleomorphic liposarcomas), leiomyosarcomas, rhabdomyosarcomas, neurofibrosarcomas, malignant peripheral nerve sheath tumors, Ewing's tumors (including Ewing's sarcoma of _{bone, extraskeletal or non bone) and primitive neuroectodermal tumors (PNET), synovial} sarcoma, hemangioendothelioma, fibrosarcoma, desmoids tumors, dermatofibrosarcoma protuberance (DFSP), malignant fibrous histiocytoma(MFH), hemangiopericytoma, _{malignant mesenchymoma, alveolar soft part sarcoma, epithelioid sarcoma, clear cell} sarcoma, desmoplastic small cell tumor, gastrointestinal stromal tumor (GIST) and _{osteosarcoma (also known as osteogenic sarcoma) skeletal and extra skeletal, and} chondrosarcoma. The compositions of the present disclosure may be used in the treatment of a lymphoma. Lymphomas which may be treated include mature B cell neoplasms, mature T cell and natural killer (NK) cell neoplasms, precursor lymphoid neoplasms, Hodgkin lymphomas, and immunodeficiency-associated lymphoproliferative disorders. Attorney Docket No.10110-450WO1 Representative mature B cell neoplasms include, but are not limited to, B-cell chronic lymphocytic leukemia/small cell lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma (such as Waldenström macroglobulinemia), splenic marginal zone lymphoma, hairy cell leukemia, plasma cell neoplasms (such as plasma cell myeloma/multiple myeloma, plasmacytoma, monoclonal immunoglobulin deposition diseases, and heavy chain diseases), extranodal marginal zone B cell lymphoma (MALT lymphoma), nodal marginal zone B cell lymphoma, follicular lymphoma, primary cutaneous follicular center lymphoma, mantle cell lymphoma, diffuse large B cell lymphoma, diffuse large B-cell lymphoma associated with chronic inflammation, Epstein- Barr virus-positive DLBCL of the elderly, lyphomatoid granulomatosis, primary mediastinal (thymic) large B-cell lymphoma, intravascular large B-cell lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, primary effusion lymphoma, large B-cell lymphoma arising in HHV8-associated multicentric Castleman’s disease, and Burkitt lymphoma/leukemia. Representative mature T cell and NK cell neoplasms include, but are not limited to, T-cell prolymphocytic leukemia, T-cell large granular lymphocyte leukemia, aggressive NK cell leukemia, adult T-cell leukemia/lymphoma, extranodal NK/T-cell lymphoma, nasal type, enteropathy-associated T-cell lymphoma, hepatosplenic T-cell lymphoma, blastic NK cell lymphoma, lycosis fungoides/Sezary syndrome, primary cutaneous CD30-positive T cell lymphoproliferative disorders (such as primary cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis), peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T cell lymphoma, and anaplastic large cell lymphoma. Representative precursor lymphoid neoplasms include B-lymphoblastic leukemia/lymphoma not otherwise specified, B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities, or T-lymphoblastic leukemia/lymphoma. Representative Hodgkin lymphomas include classical Hodgkin lymphomas, mixed cellularity Hodgkin lymphoma, lymphocyte-rich Hodgkin lymphoma, and nodular lymphocyte-predominant Hodgkin lymphoma. The compositions of the present disclosure may be used in the treatment of a Leukemia. Representative examples of leukemias include, but are not limited to, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), hairy cell leukemia (HCL), T-cell prolymphocytic leukemia, adult T-cell leukemia, clonal eosinophilias, and transient myeloproliferative disease. Attorney Docket No.10110-450WO1 The compositions of the present disclosure may be used in the treatment of a germ cell tumor, for example germinomatous (such as germinoma, dysgerminoma, and seminoma), non germinomatous (such as embryonal carcinoma, endodermal sinus tumor, choriocarcinoma, teratoma, polyembryoma, and gonadoblastoma) and mixed tumors. The compositions of the present disclosure may be used in the treatment of blastomas, for example hepatoblastoma, medulloblastoma, nephroblastoma, neuroblastoma, pancreatoblastoma, pleuropulmonary blastoma, retinoblastoma, and glioblastoma multiforme. Representative cancers which may be treated include, but are not limited to: bone and muscle sarcomas such as chondrosarcoma, Ewing’s sarcoma, malignant fibrous histiocytoma of bone/osteosarcoma, osteosarcoma, rhabdomyosarcoma, and heart cancer; brain and nervous system cancers such as astrocytoma, brainstem glioma, pilocytic astrocytoma, ependymoma, primitive neuroectodermal tumor, cerebellar astrocytoma, cerebral astrocytoma, glioma, medulloblastoma, neuroblastoma, oligodendroglioma, pineal astrocytoma, pituitary adenoma, and visual pathway and hypothalamic glioma; breast cancers including invasive lobular carcinoma, tubular carcinoma, invasive cribriform carcinoma, medullary carcinoma, male breast cancer, Phyllodes tumor, and inflammatory breast cancer; endocrine system cancers such as adrenocortical carcinoma, islet cell carcinoma, multiple endocrine neoplasia syndrome, parathyroid cancer, phemochromocytoma, thyroid cancer, and Merkel cell carcinoma; eye cancers including uveal melanoma and retinoblastoma; gastrointestinal cancers such as anal cancer, appendix cancer, cholangiocarcinoma, gastrointestinal carcinoid tumors, colon cancer, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, hepatocellular cancer, pancreatic cancer, and rectal cancer; genitourinary and gynecologic cancers such as bladder cancer, cervical cancer, endometrial cancer, extragonadal germ cell tumor, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, penile cancer, renal cell carcinoma, renal pelvis and ureter transitional cell cancer, prostate cancer, testicular cancer, gestational trophoblastic tumor, urethral cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor; head and neck cancers such as esophageal cancer, head and neck cancer, nasopharyngeal carcinoma, oral cancer, oropharyngeal cancer, paranasal sinus and nasal cavity cancer, pharyngeal cancer, salivary gland cancer, and hypopharyngeal cancer; hematopoietic cancers such as acute biphenotypic leukemia, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute myeloid leukemia, acute Attorney Docket No.10110-450WO1 myeloid dendritic cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell prolymphocytic leukemia, Burkitt’s lymphoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, cutaneous T- cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, hepatosplenic T-cell lymphoma, Hodgkin’s lymphoma, hairy cell leukemia, intravascular large B-cell lymphoma, large granular lymphocytic leukemia, lymphoplasmacytic lymphoma, lymphomatoid granulomatosis, mantle cell lymphoma, marginal zone B-cell lymphoma, Mast cell leukemia, mediastinal large B cell lymphoma, multiple myeloma/plasma cell neoplasm, myelodysplastic syndroms, mucosa-associated lymphoid tissue lymphoma, mycosis fungoides, nodal marginal zone B cell lymphoma, non-Hodgkin lymphoma, precursor B lymphoblastic leukemia, primary central nervous system lymphoma, primary cutaneous follicular lymphoma, primary cutaneous immunocytoma, primary effusion lymphoma, plasmablastic lymphoma, Sezary syndrome, splenic marginal zone lymphoma, and T-cell prolymphocytic leukemia; skin cancers such as basal cell carcinoma, squamous cell carcinoma, skin adnexal tumors (such as sebaceous carcinoma), melanoma, Merkel cell carcinoma, sarcomas of primary cutaneous origin (such as dermatofibrosarcoma protuberans), and lymphomas of primary cutaneous origin (such as mycosis fungoides); thoracic and respiratory cancers such as bronchial adenomas/carcinoids, small cell lung cancer, mesothelioma, non-small cell lung cancer, pleuropulmonary blastoma, laryngeal cancer, and thymoma or thymic carcinoma; HIV/AIDs-related cancers such as Kaposi sarcoma; epithelioid hemangioendothelioma; desmoplastic small round cell tumor; and liposarcoma. Compounds and compositions disclosed herein can be locally administered at one or more anatomical sites, such as sites of unwanted cell growth (such as a tumor site or benign skin growth, e.g., injected or topically applied to the tumor or skin growth), optionally in combination with a pharmaceutically acceptable carrier such as an inert diluent. Compounds and compositions disclosed herein can also be systemically administered, such as intravenously or orally, optionally in combination with a pharmaceutically acceptable carrier, such as an inert diluent or an assimilable edible carrier for oral delivery. In addition, the active compound can be incorporated into sustained-release preparations and/or devices. For the treatment of oncological disorder, compounds, agents, and compositions disclosed herein can be administered to a patient in need of treatment prior to, subsequent to, or in combination with other antitumor or anticancer agents or substances (e.g., Attorney Docket No.10110-450WO1 chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, cytotoxic agents, etc.) and/or with radiation therapy and/or with surgical treatment to remove a tumor. For example, compounds, agents, and compositions disclosed herein can be used in methods of treating cancer wherein the patient is to be treated or is or has been treated with mitotic inhibitors such as taxol or vinblastine, alkylating agents such as cyclophosphamide or ifosfamide, antimetabolites such as 5-fluorouracil or hydroxyurea, DNA intercalators such as adriamycin or bleomycin, topoisomerase inhibitors such as etoposide or camptothecin, antiangiogenic agents such as angiostatin, antiestrogens such as tamoxifen, and/or other anti-cancer drugs or antibodies, such as, for example, imatinid or trastuzumab. These other substances or radiation treatments can be given at the same time as or at different times from the compounds disclosed herein. Examples of other suitable chemotherapeutic agents include, but are not limited to, altretamine, bleomycin, bortezomib, busulphan, calcium folinate, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, crisantaspase, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, epirubicin, etoposide, fludarabine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, liposomal doxorubicin, lomustine, melphalan, mercaptopurine, methotrexate, mitomycin, mitoxantrone, oxaliplatin, paclitaxel, pentostatin, procarbazine, raltitrexed, streptozocin, tegafur-uraxil, temozolomide, thiotepa, tioguanine/thioguanine, topotexan, treosulfan, vinblastine, vincristine, vindesine, and vinorelbine. Examples of suitable immunotherapeutic agents include, but are not limited to, alemtuzumab, cetuximab, gemtuzumab, iodine 131 tositumomab, rituximab, and trastuzumab. Cytotoxic agents include, for example, radioactive isotopes and toxins of bacterial, fungal, plant, or animal origin. Also disclosed are methods of treating an oncological disorder comprising administering an effective amount of a compound described herein prior to, subsequent to, and/or in combination with administration of a chemotherapeutic agent, an immunotherapeutic agent, a radiotherapeutic agent, or radiotherapy. Additional Aspects In view of the described compounds and methods, certain more particularly described aspects of the disclosure are described below. These particularly recited aspects should not, however, be interpreted to have any limiting effect on any different claims containing different or more general teachings described herein or that the particular aspects Attorney Docket No.10110-450WO1 are somehow limited in some way other than the inherent meanings of the language literally used therein. Aspect 1. A compound of Formula I A-L-B

or a pharmaceutically acceptable salt or derivative thereof; wherein: A is selected from

a double bond; B is an E3 ubiquitin ligase-recruiting moiety;

m1 is 1, 2, 3, 4, or 5; L¹ and L² are independently selected from C1-C6 alkyl and

; m2 is 1, 2, or 3; Q¹, Q³, Q⁵, and Q⁶ are independently selected from 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more groups selected from Z as allowed by valency; Q² is selected from 3- to 8-membered monocyclic or bicyclic heterocycle, 5- to 10- membered monocyclic or bicyclic heteroaryl, and C3-C9 monocyclic or bicyclic cycloalkyl, Attorney Docket No.10110-450WO1 each of which may be optionally substituted with one or more groups selected from Z as allowed by valency;

X¹ is selected from -N(R^x)-, -O-, -S-, and 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more groups selected from Z; Y¹ is selected from O and NH; X² is absent or -N(R^x)-; Z is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, R^xO-(C0-C3 alkyl)-, R^xS-(C0- C3 alkyl)-, (R^xR^yN)-(C0-C3 alkyl)-, R^xO-C(O)-(C0-C3 alkyl)-, R^xS-C(O)-(C0-C3 alkyl)-, (R^xR^yN) C(O)-(C0-C3 alkyl)-, R^xO-S(O)2-(C0-C3 alkyl)-, (R^xR^yN) S(O)2-(C0-C3 alkyl)-, R^zC(O)-O-(C0-C3 alkyl)-, R^zC(O)-(R^xN)-(C0-C3 alkyl)-, R^zS(O)2-O-(C0-C3 alkyl)-, R^zS(O)2- (R^xN)-(C0-C3 alkyl)-, R^zC(O)-(C0-C6 alkyl)-, R^zS(O)-(C0-C3 alkyl)-, and R^zS(O)2-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency; R^x and R^y are independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; R^z is independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OR^x, -SR^x, and -NR^xR^y, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Attorney Docket No.10110-450WO1 Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. Aspect 2. The compound of aspect 1, wherein L is -L¹-Q¹-L²-. Aspect 3. The compound of aspect 2, wherein Q¹ is selected from

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. Aspect 4. The compound of aspect 2 or aspect 3, wherein L¹ is C1-C6 alkyl. Aspect 5. The compound of aspect 2 or aspect 3, wherein L¹ is

. Aspect 6. The compound of any one of aspects 2-5, wherein L² is C1-C6 alkyl. Aspect 7. The compound of any one of aspects 2-5, wherein L²

. Aspect 8. The compound of aspect 1, wherein L is -L¹-Q²-L²-Q³-. Aspect 9. The compound of aspect 8, wherein Q² is selected from

,

wherein X³ and X⁴ are independently selected from CH and N; and n1 and n2 are independently 1 or 2. Attorney Docket No.10110-450WO1 Aspect 10. The compound of aspect 8, wherein Q² is

. Aspect 11. The compound of any one of aspects 8-10, wherein Q³ is selected from

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. Aspect 12. The compound of any one of aspects 8-11, wherein L¹ is C1-C6 alkyl. Aspect 13. The compound of any one of aspects 8-11, wherein L¹ is

. Aspect 14. The compound of any one of aspects 8-13, wherein L² is C1-C6 alkyl. Aspect 15. The compound of any one of aspects 8-13, wherein L² is

. Aspect 16. The compound of aspect 1, wherein L is -L¹-Q⁴-L²-. Aspect 17. The compound of aspect 16, wherein X¹ is selected from -NH-, -O-, -S-,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. Aspect 18. The compound of aspect 16 or aspect 17, wherein Y¹ is O. Aspect 19. The compound of aspect 16 or aspect 17, wherein Y¹ is NH. Aspect 20. The compound of any one of aspects 16-19, wherein X² is absent. Aspect 21. The compound of any one of aspects 16-19, wherein X² is NH. Aspect 22. The compound of any one of aspects 16-21, wherein L¹ is C1-C6 alkyl. Attorney Docket No.10110-450WO1 Aspect 23. The compound of any one of aspects 16-21, wherein L¹

. Aspect 24. The compound of any one of aspects 16-23, wherein L² is C1-C6 alkyl. Aspect 25. The compound of any one of aspects 16-23, wherein L² is

. Aspect 26. The compound of aspect 1, wherein L is -Q⁵-L¹-Q⁶-. Aspect 27. The compound of aspect 26, wherein Q⁵ is selected from

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. Aspect 28. The compound of aspect 26 or aspect 27, wherein Q⁶ is selected from

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. Aspect 29. The compound of any one of aspects 26-28, wherein L¹ is C1-C6 alkyl. Aspect 30. The compound of any one of aspects 26-28, wherein L¹ is

. Aspect 31. The compound of any one of aspects 1-30, wherein B is selected from: Attorney Docket No.10110-450WO1

wherein: X⁵ is a bond or selected from -NH-, -O-, and -CH2-; R¹ is hydrogen or -CH2-O-C(=O)-O-(C1-C6 alkyl); X⁶ is selected from CH and N; R² is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and X⁷ is selected from O and NH. Aspect 32. A pharmaceutical composition comprising a compound of any one of aspects 1-31, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient. Aspect 33. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of aspects 1-31, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of aspect 32. Aspect 34. The method of aspect 35, wherein the cancer is a TAF1-associated cancer. A number of aspects of the disclosure have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the disclosure. Accordingly, other aspects are within the scope of the following claims. By way of non-limiting illustration, examples of certain aspects of the present disclosure are given below. Attorney Docket No.10110-450WO1 EXAMPLES The following examples are set forth below to illustrate the compounds, compositions, and methods claimed herein, along with associated methods and results according to the disclosed subject matter. These examples are not intended to include all aspects of the subject matter disclosed herein but rather to illustrate representative methods and results. These examples are not intended to exclude equivalents and variations of the present disclosure, which are apparent to one skilled in the art. Efforts have been made to ensure accuracy with respect to numbers (e.g., amounts, temperature, etc.), but some errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric. There are numerous variations and combinations of reaction conditions, e.g., component concentrations, temperatures, pressures, and other reaction ranges and conditions, that can be used to optimize the product purity and yield obtained from the described process. Only reasonable and routine experimentation will be required to optimize such process conditions. Example 1. Synthesis of Compounds General experimental information: Reagents were purchased at the highest commercial quality and used without further purification, unless otherwise stated. Anhydrous tetrahydrofuran (THF), 1,4-dioxane (dioxane), acetonitrile (MeCN), dichloromethane (DCM), and dimethylformamide (DMF) were obtained by passing the previously degassed solvent through an activated alumina column (PPT Glass Contour Solvent Purification System). Anhydrous dimethylsulfoxide (DMSO) and dimethylacetamide (DMA) was purchased from Acros Organics. Yields refer to chromatographically and spectroscopically (1H NMR) homogeneous material, unless otherwise stated. Reactions were monitored by LC–MS or thin layer chromatography (TLC) carried out on 250 µm SiliCycle SiliaPlates (TLC Glass–Backed TLC Extra Hard Layer, 60 Å), using shortwave UV light as the visualizing agent or Iodine chamber, p-anisaldehyde, phosphomolybdic acid (PMA), KMnO4, Ninhydrin, Cerium ammonium molybdate (CAM) with heat as developing agents. Flash column chromatography was performed with a Biotage Isolera One (ZIP or SNAP Ultra cartridges) or with traditional glass flash columns using SiliCycle SiliaFlash® P60 (particle size 40 – 63 µm). NMR spectra were recorded on a Bruker AscendTM 500 MHz instrument or Bruker Neo600 600MHz spectrometer and Attorney Docket No.10110-450WO1 were calibrated using residual undeuterated solvent as an internal reference (CDCl3: 7.26 ppm 1H NMR, 77.16 ppm 13C NMR; DMSO–d6: 2.50 ppm 1H NMR, 39.5ppm 13CNMR). The following abbreviations were used to explain NMR peak multiplicities: s = singlet, d= doublet, t = triplet, q = quartet, dd = doublet of doublet, ddd = doublet of doublet of doublet, dddd = doublet of doublet of doublet of doublet, ddddd = doublet of doublet of doublet of doublet of doublet, tt = triplet of triplet, ddt = doublet of doublet of triplet, m = multiplet, br = broad, hept = heptet. High-resolution mass spectra (HRMS) were recorded on an Agilent 6230 LC–MS TOF mass spectrometer. General scheme:

Compound 1 was prepared from known procedures.^1,2 Linkers of the general structure 2 were prepared from known procedures referenced below unless otherwise specified below. In a 2-dram vial equipped with a stir bar, 1 was dissolved in DMF (0.2 M) then K2CO3 (2 eq.) was added and stirred at room temperature for 15 minutes. Electrophilic linker of general structure 2 (1.2 eq.) was added and the reaction stirred at room temperature for 12 hours to achieve full consumption of 1. EtOAc (5 x volume of DMF) was added, the Attorney Docket No.10110-450WO1 reaction mixture filtered through a pad of celite, and the filtrate concentrated. The crude material was further purified by column chromatography using hexanes/EtOAc (0 to 80% EtOAc gradient) to provide the desired products (3). General procedure 2 (GP-2)

Step 1: In a 2-dram vial equipped with a stir bar, compounds of general structure 3 (1 eq.) were dissolved in MeOH (0.1 M) followed by the addition of NaOH (1 M, 4.3 eq.). The resulting reaction mixture was heated to 70 ºC for 6-15 hours until full consumption of 3 then cooled to room temperature. The solvent was removed under reduced pressure and the crude material was taken up in DCM. Water and NaOH (1 M) was added to adjust the pH (>10). The aqueous layer was extracted with DCM (2 x) and discarded. The remaining aqueous layer was acidified to pH 3-2 with HCl (2 M), let stand for 5 minutes. The resulting solid was collected by filtration while rinsing with water then dried under vacuum to give 4 _{as the main regioisomer ( 10:1).} Step 2: The product of step 1 was dissolved in DMF (0.1 M) then morpholine (2 eq.), Et3N (2 eq.) and HATU (2 eq.) were added then warmed to 40 ºC for 2-6 hours until full conversion was achieved. The solvent was removed under reduced pressure and the crude material was taken up in DCM then sat. aq. NH4Cl was added. The aqueous layer was extracted with DCM (3 x), combined organic layers dried over Na2SO4, filtered and concentrated. Further purification by column chromatography using DCM/MeOH (0 to 5% MeOH gradient) provided the desired products (4). General procedure 3 (GP-3) Attorney Docket No.10110-450WO1

In a 1-dram vial equipped with a stir bar, compounds of general structure 4 (1 eq.) were dissolved in THF followed by the addition of 5 (1 eq.), CuI (0.5 eq.), and DIPEA (2 eq.) The reaction mixture was degassed with argon while sonicating for 3 minutes then stirred at room temperature for 24 hours until full consumption of 4. The solvent was removed under reduced pressure and the crude material was purified by reverse phase column chromatography using H2O (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN gradient) to provide the desired products (6). General procedure 4 (GP-4)

In a 1-dram vial equipped with a stir bar, compounds of general structure 4 (1 eq.) were dissolved in THF followed by the addition of 7 (1 eq.), CuSO4 (0.2 eq.), sodium ascorbate (0.2 eq.), and water (5% v/v). The reaction mixture was degassed with argon while sonicating for 3 minutes then stirred at room temperature for 2-8 hours until full consumption of 4. The reaction mixtures were directly absorbed to silica gel and purified by column chromatography using DCM/MeOH (0-15% MeOH gradient) to provide the desired products (8). Some examples were further purified by reverse phase column Attorney Docket No.10110-450WO1 chromatography using H2O (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN gradient) to provide the desired products (8). General procedure 5 (GP-5)

In a 1-dram vial equipped with a stir bar, compounds 9 (1 eq.) and 10 (1.2 eq) were dissolved in MeOH (0.09 M) followed by the addition of NaOAc (3 eq.), AcOH (0.5 eq.) and NaCNBH3 (3 eq.) then stirred at room temperature for 2 hours or until full consumption of 9. The reaction was quenched with water, extracted with EtOAc (3 x) then CHCl3/IPA (3:1, 3 x), combined organic layers were dried over Na2SO4, filtered and concentrated. Further purification by column chromatography using DCM/MeOH (0 to 10% MeOH gradient) provided the desired products (11). Purification by reverse phase column chromatography using water (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN) was required if 9 was used as a mixture of regioisomers. Compound characterization:

GP-1 was followed using 1 (250 mg, 0.484 mmol, 1 eq.) and electrophilic linker 2a (111 mg, 580 mmol, 1.2 eq.) to give 3a (249 mg, 0.397 mmol, 82% yield) as a colorless foam after silica gel column chromatography using hexanes/EtOAc (0 to 80% EtOAc gradient) containing 5-10% of an undesired regioisomer. Attorney Docket No.10110-450WO1 Electrophilic linker 2a was prepared from a known procedure.³ Physical characteristic:

GP-2 was followed using 3a (234 mg, 0.373 mmol, 1 eq.) in step 1 to give the desired intermediate (139 mg, 0.303 mmol, 81% yield) as a white solid that was used in the next step without further purification or characterization. In step 2, intermediate (102 mg, 0.222 mmol, 1 eq.) was used to give 4a (99 mg, 0.187 mmol, 84% yield) as a colorless foam after silica gel column chromatography using DCM/MeOH (0 to 5% MeOH gradient). Physical characteristic: colorless foam. TLC: Rf = 0.30 (5% MeOH in DCM, UV). ¹H NMR: (500 MHz, CDCl3) 11.06 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.54 (d, J = 10.6 Hz, 2H), 7.28 – 7.27 (m, 1H), 6.46 (s, 1H), 5.86 (dt, J = 10.2, 6.9 Hz, 1H), 5.15 – 5.04 (m, 2H), 4.25 – 4.21 (m, 4H), 3.72 (s, 8H), 3.28 (t, J = 6.6 Hz, 2H), 2.63 – 2.59 (m, 2H), 1.97 – 1.93 (m, 2H), 1.66 – 1.61 (m, 2H), 1.48 – 1.43 (m, 2H) ppm. LC–MS: M+H⁺ = 528.8

GP-3 was followed using 4a (39 mg, 0.074 mmol, 1 eq.) and 5 (28 mg, 0.074 mmol, 1 eq.). Purification by reverse phase column chromatography using water (0.1% formic Attorney Docket No.10110-450WO1 acid)/MeCN (0.1% formic acid) (0% to 50% MeCN) provided ZS3-030 (24 mg, 0.026 mmol, 36% yield) as a yellow foam. Compound 5 was prepared according to a reported procedure.⁴ Physical characteristics: yellow foam. TLC: Rf = 0.43

10.46 (s, 1H), 8.97 (s, 1H), 7.96 (s, 1H), 7.65 (s, 1H), 7.56 – 7.50 (m, 3H), 7.45 (s, 1H), 7.37 (d, J = 7.1 Hz, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.45 (t, J = 2.5 Hz, 1H), 5.88 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.15 – 5.02 (m, 2H), 4.95 (dd, J = 12.1, 5.3 Hz, 1H), 4.33 (t, J = 6.9 Hz, 2H), 4.25 – 4.19 (m, 4H), 3.74 (d, J = 10.5 Hz, 8H), 3.37 – 3.26 (m, 4H), 2.91 – 2.74 (m, 3H), 2.70 (d, J = 10.0 Hz, 4H), 2.61 (q, J = 7.2 Hz, 2H), 2.09 (ddt, J = 10.1, 5.3, 2.6 Hz, 1H), 1.95 (dt, J = 7.7, 4.0 Hz, 5H), x1.39 – 1.32 (m, 4H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.3, 170.8, 168.7, 167.4, 166.7, 154.5, 150.2, 144.2, 142.6, 135.6, 134.6, 134.4, 134.1, 130.4, 129.8, 129.7, 129.2, 126.7, 124.2, 123.3, 122.7, 120.6, 117.5, 117.3, 115.8, 112.4, 108.3, 103.6, 66.9, 53.1, 52.7, 50.8, 49.8, 49.2, 48.5, 45.1, 34.2, 31.5, 29.7, 29.2, 23.9, 22.7, 14.1 ppm. HRMS: Calc’d for C48H53N12O7 [M+H⁺] 909.4155; found 909.4161.

GP-1 was followed using 1 (150 mg, 0.290 mmol, 1 eq.) and electrophilic linker 2b (120 mg, 348 mmol, 1.2 eq.) to give 3b (195 mg, 0.290 mmol) as an amber oil that was used without further purification or characterization. The crude material contained 5-10% of an undesired regioisomer. Electrophilic linker 2b was prepared from a known procedure.⁵ Physical characteristics: amber oil (crude). TLC: Rf = 0.33 (3% MeOH in DCM, UV) LC–MS: M+H⁺ = 673.8 Attorney Docket No.10110-450WO1

GP-2 was followed using 3b (196 mg, 0.290 mmol, 1 eq.) in step 1 to give the desired intermediate (88 mg, 0.174 mmol, 60% yield) as a white solid and single regioisomer that was used in the next step without further purification or characterization. In step 2, the same intermediate (75 mg, 0.148 mmol, 1 eq.) was used to give 4b (80.4 mg, 0.140 mmol, 94% yield) as a tan foam after column chromatography using DCM/MeOH (0 to 6% MeOH gradient). Physical characteristic: tan foam TLC: Rf = 0.30 (5% MeOH in DCM, UV) LC–MS: M+H⁺ = 574.8

GP-3 was followed using 4b (40 mg, 0.070 mmol, 1 eq.) and 7 (22 mg, 0.070 mmol, 1 eq.). Purification by column chromatography using DCM/MeOH (0% to 7% MeOH) provided ZS3-037 (49 mg, 0.055 mmol, 79% yield, as a yellow oil. Compound 7 was prepared according to a reported procedure.⁶ Physical characteristics: yellow oil. TLC: Rf = 0.39 (10% MeOH/DCM, UV) ¹H NMR: (500 MHz, CDCl3) 10.69 (s, 1H), 9.54 (s, 1H), 8.09 (s, 1H), 7.64 (d, J = 1.4 Hz, 1H), 7.57 (s, 1H), 7.49 (d, J = 1.4 Hz, 1H), 7.42 – 7.36 (m, 2H), 7.22 (t, J = 2.8 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.75 (t, J = 6.0 Hz, 1H), 6.38 (t, J = 2.5 Hz, 1H), 5.89 – 5.78 (m, 1H), 5.12 – 4.99 (m, 2H), 4.93 – 4.85 (m, 1H), 4.58 – 4.47 (m, 2H), 4.39 – 4.31 (m, 4H), 4.18 (t, J = 7.4 Hz, 2H), 3.76 – 3.61 (m, 10H), 3.44 (t, J = 4.3 Hz, 2H), 3.40 – 3.30 (m, 2H), 2.87 – 2.77 (m, 1H), 2.76 – 2.68 (m, 2H), 2.57 (q, J = 7.2 Hz, 2H), 2.13 – 2.03 (m, 1H), 2.01 – 1.84 (m, 2H) ppm. HRMS: Calc’d for C45H48N11O9 [M+H⁺] 886.3631; found 886.3637. Attorney Docket No.10110-450WO1

GP-1 was followed using 1 (200 mg, 0.387 mmol, 1 eq.) and electrophilic linker 2c (181 mg, 465 mmol, 1.2 eq.) to give crude 3c (278 mg, 0.387 mmol) as an amber oil that was used without further purification or characterization. The crude material contained 5-10% of an undesired regioisomer. Electrophilic linker 2c was prepared from a known procedure.⁷ Physical characteristics: amber oil (crude). TLC: Rf = 0.29 (3% MeOH in DCM, UV) LC–MS: M+H⁺ = 717.7

GP-2 was followed using 3c (278 mg, 0.387 mmol, 1 eq.) in step 1 to give the desired intermediate (111 mg, 0.202 mmol, 52% yield) as a white solid and single regioisomer that was used in the next step without further purification or characterization. In step 2, the same intermediate (80 mg, 0.146 mmol, 1 eq.) was used to give 4c (81 mg, 0.131 mmol, 90% yield) as a tan foam after silica gel column chromatography using DCM/MeOH (0 to 6% MeOH gradient). Physical characteristics: tan foam. TLC: Rf = 0.24 (5% MeOH in DCM, UV). LC–MS: M+H⁺ = 618.8 Attorney Docket No.10110-450WO1

Step 1: In a 1-dram vial equipped with a stir bar was added 4c (55 mg, 0.089 mmol, 1 eq.) followed by THF (0.9 mL, 0.1 M), PPh3 (26 mg, 0.098 mmol, 1.1 eq.) and H2O (2.4 L, 0.133 mmol, 1.5 eq.). The vessel was capped and stirred at room temperature for 8 hours until full consumption of 4c. The solvent was removed under reduced pressure to afford a crude mixture (53 mg) containing the desired amine and PPh3O as a light-yellow oil, which was used in the next step without further purification or characterization. Physical characteristics: light-yellow oil. TLC: Rf = 0.39 (10% MeOH in DCM). LC–MS: M+H⁺ = 592.8 Step 2: In a 1-dram reaction vial equipped with a stir bar was added crude mixture containing amine intermediate from step 1 (53 mg, 0.089 mmol, 1 eq.) followed by DMA (0.9 mL, 0.1 M), 12 (24.6 mg, 0.089 mmol, 1 eq.) and DIPEA (46.5 L, 0.267 mmol, 3 eq.). The reaction vessel was capped then heated to 80 ºC for 10 hours until full consumption of 12, cooled to room temperature, and the solvent removed under reduced pressure. The crude material was adsorbed to silica gel and purified by silica gel column chromatography using DCM/MeOH (0 to 8% MeOH) to give ZS3-039 (43 mg, 0.051 mmol, 57% yield) as a yellow oil. Compound 13 was prepared according to a reported procedure.⁸ Physical characteristics: yellow oil. TLC: Rf = 0.23 (5% MeOH in DCM, UV) ¹H NMR: (500 MHz, CDCl3) 10.64 (s, 1H), 9.35 (s, 1H), 8.16 (s, 1H), 7.63 (s, 1H), 7.58

1.4 Hz, 1H), 7.51 (d, J = 1.5 Hz, 1H), 7.43 (dd, J = 8.5, 7.1 Hz, 1H), 7.25 (dd, J = 5.3, 2.6 Hz, 1H), 7.06 (d, J = 7.1 Hz, 1H), 6.85 (d, J = 8.6 Hz, 1H), 6.48 – 6.43 (m, 2H), 5.92 – 5.81 (m, 1H), 5.16 – 5.00 (m, 2H), 4.85 (dd, J = 12.2, 5.4 Hz, 1H), 4.36 (t, J = 5.0 Hz, 2H), 4.20 (t, J = 7.4 Hz, 2H), 3.83 (t, J = 5.0 Hz, 2H), 3.77 – 3.69 (m, 4H), 3.66 (t, J = 5.3 Hz, 2H), 3.59 (d, J = 11.5 Hz, 8H), 3.40 (q, J = 5.4 Hz, 2H), 2.84 – 2.79 (m, 1H), 2.76 – 2.66 (m, 2H), 2.60 (q, J = 7.2 Hz, 2H), 2.07 (dt, J = 13.3, 3.9 Hz, 1H), 1.89 (s, 4H) ppm. Attorney Docket No.10110-450WO1 ¹³C NMR: (126 MHz, CDCl3) 171.5, 170.9, 169.3, 168.9, 167.6, 154.6, 146.7, 145.3, 142.4, 136.0, 134.6, 134.5, 132.5, 130.0, 130.0, 129.5, 128.9, 124.2, 120.5, 117.4, 116.7, 112.7, 111.6, 110.2, 108.5, 103.6, 70.8, 70.7, 70.6, 70.6, 69.5, 69.2, 67.0, 48.9, 48.5, 45.2, 42.3, 34.2, 31.5, 22.8 ppm. HRMS: Calc’d for C44H48N8O10 [M+H⁺] 849.3566; found 849.3563.

GP-1 was followed using 1 (214 mg, 0.413 mmol, 1 eq.) and electrophilic linker 2d (126 mg, 497 mmol, 1.2 eq.) to give 3d (246 mg, 0.366 mmol, 88% yield) as a light-yellow oil after silica gel column chromatography using DCM/acetone (0% to 20% acetone gradient containing 5-10% of an undesired regioisomer. Purification of the major isomer was performed by reverse phase column chromatography using water (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN gradient). Electrophilic linker 2d was prepared from a known procedure.⁹ Physical characteristics: light-yellow oil. TLC: Rf = 0.31 (60% EtOAc in hexanes, UV)

NMR: (500 MHz, CDCl3) 8.13 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 8.02 – 7.98 (m, 3H), 7.90 (d, J = 3.5 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.53 (d, J = 3.5 Hz, 1H), 5.77 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.07 – 4.94 (m, 2H), 4.81 (t, J = 4.7 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H), 3.98 (s, 3H), 3.96 – 3.92 (m, 2H), 3.85 – 3.80 (m, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.98 – 1.89 (m, 2H), 1.67 – 1.60 (m, 2H), 1.46 – 1.34 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 167.29, 152.54, 145.23, 145.02, 144.67, 136.27, 136.09, 134.40, 134.18, 133.00, 130.79, 129.41, 128.62, 127.72, 125.04, 123.24, 123.09, 117.44, 111.22, 110.86, 106.32, 104.40, 64.86, 52.39, 48.79, 45.49, 33.83, 33.64, 29.80, 28.94, 26.72, 23.78, 21.68 ppm. LC–MS: M+H⁺ = 672.6 Attorney Docket No.10110-450WO1

GP-2 was followed using 4c (202 mg, 0.30 mmol, 1 eq.) in step 1 to give the desired intermediate (112 mg, 0.222 mmol, 74% yield) as a white solid and single regioisomer that was used in the next step without further purification or characterization. In step 2, the same intermediate (110 mg, 0.218 mmol, 1 eq.) was used to give 4d (119 mg, 0.207 mmol, 95% yield) as an off-white foam after column chromatography using DCM/MeOH (0 to 6% MeOH gradient). Physical characteristics: off-white foam. TLC: R^f = 0.29 (5% MeOH in DCM, UV) ¹H NMR: (500 MHz, CDCl3) 10.71 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J = 12.8, 1.2 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.48 (t, J = 2.4 Hz, 1H), 5.89 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.13 (dd, J = 17.1, 1.5 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.83 (t, J = 4.7 Hz, 1H), 4.23 (dt, J = 12.8, 7.2 Hz, 4H), 3.98 – 3.93 (m, 2H), 3.90 – 3.52 (m, 10H), 2.63 (q, J = 7.1 Hz, 2H), 1.99 – 1.90 (m, 2H), 1.68 – 1.62 (m, 2H), 1.47 – 1.36 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 170.85, 154.60, 144.17, 142.63, 134.59, 134.47, 130.18, 129.83, 129.61, 129.21, 126.65, 124.31, 120.51, 117.42, 112.52, 108.30, 104.41, 103.56, 66.97, 64.87, 48.47, 45.40, 34.21, 33.66, 29.77, 28.97, 26.81, 23.81 ppm. LC–MS: M+H⁺ = 573.7

In a 20 mL septum capped vial equipped with a stir bar was added 4d (365 mg, 0.636 mmol, 1 eq.) followed by acetone/H2O (5.3 mL/1 mL, 0.1 M) and p-TSA (127 mg, 0.668 mmol, 1.05 eq.). The reaction mixture stirred at room temperature for 5 hours then the solvent was removed under reduced pressure. The crude was taken up in EtOAc (100 mL) and washed with saturated NaHCO3 (3 x 15 mL), dried over Na2SO4, filtered and concentrated. Attorney Docket No.10110-450WO1 Purification by silica gel column chromatography using hexanes/Acetone (0 to 40% acetone gradient) provided 13 (309 mg, 0.583 mmol, 92% yield) as a colorless oil which was used immediately in the next step. Physical characteristics: colorless oil. TLC: Rf = 0.22 (20% acetone in hexanes, UV) LC–MS: M+H⁺ = 529.7

GP-5 was followed using 13 (40 mg, 0.076 mmol, 1 eq.) and amine nucleophile 10a (n = 2) (44 mg, 0.091 mmol, 1.2 eq.) to give ZS3-046 (41 mg, 0.046 mmol, 61% yield) as a yellow solid after reverse phase column chromatography using water (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN gradient). Amine nucleophile 10a (n = 2) was prepared from a known procedure.¹⁰ Physical characteristics: yellow solid. TLC: Rf = 0.39 (10% MeOH in DCM, UV)

NMR: (500 MHz, CDCl3) 10.09 (s, 1H), 8.98 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.55 – 7.45 (m, 3H), 7.11 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 2.2 Hz, 1H), 6.29 (t, J = 5.7 Hz, 1H), 5.88 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.17 – 5.09 (m, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.92 (dd, J = 12.3, 5.4 Hz, 1H), 4.23 (q, J = 6.6 Hz, 4H), 3.74 (s, 8H), 3.24 (d, J = 10.8 Hz, 2H), 3.21 – 3.14 (m, 2H), 2.92 – 2.84 (m, 1H), 2.80 – 2.70 (m, 2H), 2.62 (q, J = 7.1 Hz, 2H), 2.59 – 2.53 (m, 2H), 2.28 – 2.17 (m, 2H), 2.16 – 2.09 (m, 1H), 1.92 (q, J = 6.6 Hz, 2H), 1.85 (d, J = 12.7 Hz, 2H), 1.73 – 1.50 (m, 5H), 1.36 – 1.27 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.3, 170.8, 169.6, 168.8, 167.7, 167.5, 154.5, 146.8, 144.3, 142.7, 136.2, 134.5, 134.4, 132.5, 130.3, 129.9, 129.5, 129.2, 126.5, 124.3, 120.5, 117.5, 116.6, 112.7, 111.8, 110.2, 108.4, 103.8, 67.0, 57.6, 52.4, 49.0, 48.5, 47.8, 45.4, 35.3, 34.2, 31.5, 29.5, 28.6, 28.4, 26.9, 26.4, 24.8, 22.9 ppm. HRMS: Calc’d for C49H57N9O7 [M+H⁺] 884.4454; found 884.4449. Attorney Docket No.10110-450WO1

GP-5 was followed using 13 (11 mg, 0.021 mmol, 1 eq.) and amine nucleophile 10b (n = 1) (11 mg, 0.025 mmol, 1.2 eq.) to give ZS3-047 (10 mg, 0.012 mmol, 56% yield) as a yellow oil after preparative TLC using DCM/MeOH (10% MeOH). Physical characteristics: yellow oil. TLC: Rf = 0.37 (10% MeOH in DCM, UV) ¹H NMR: (500 MHz, MeOD) 8.31 (s, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.63 (s, 1H), 7.57 – 7.51 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 7.06 (t, J = 8.0 Hz, 2H), 6.42 (d, J = 2.8 Hz, 1H), 5.96 – 5.82 (m, 1H), 5.14 – 5.07 (m, 1H), 5.07 – 5.01 (m, 2H), 4.39 (t, J = 6.9 Hz, 2H), 4.23 (t, J = 7.4 Hz, 2H), 3.91 – 3.67 (m, 7H), 3.65 – 3.58 (m, 5H), 3.51 (d, J = 6.8 Hz, 2H), 3.30 – 3.24 (m, 2H), 2.96 – 2.79 (m, 2H), 2.75 – 2.66 (m, 2H), 2.66 – 2.58 (m, 4H), 2.12 – 2.04 (m, 1H), 1.99 – 1.89 (m, 2H), 1.37 – 1.31 (m, 9H) ppm. HRMS: Calc’d for C⁴⁷H⁵³N⁹O⁷ [M+H⁺] 856.4141; found 856.4139. Amine nucleophile 10b (n = 1) was prepared from the following procedure.

Step 1: In a 20 mL septum capped vial equipped with a stir bar was added 12 (102 mg, 0.548 mmol, 1 eq.) followed by DMA (5.5 mL, 0.1 M), 14 (151 mg, 0.548 mmol, 1 eq.), and DIPEA (0.286 mL, 1.64 mmol, 3 eq.) then capped and heated to 80 ºC for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added then extracted with EtOAc (3 x 20 mL). Combined organic layers were washed with water (10 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel Attorney Docket No.10110-450WO1 column chromatography using DCM/MeOH (0 to 3%) provided the desired intermediate (104 mg, 0.235 mmol, 43% yield) as a yellow oil that was immediately used in step 2. Physical characteristics: yellow oil. TLC: Rf = 0.51 (5% MeOH in DCM, UV). LC–MS: M-H = 440.7 Step 2: The intermediate from step 1 (32 mg, 0.073 mmol, 1 eq.) was added to a 1-dram vial equipped with a stir bar followed by DCM (0.73 mL) and TFA (0.553 mL, 7.23 mmol, 100 eq.) then stirred at room temperature for 1.5 hours. The solvent and excess TFA were removed under vacuum to give 10b (31 mg, 0.068 mmol, 94% yield) as a yellow solid that was used immediately for the synthesis of ZS3-047 using GP-5. References for Example 1 1. Wang, S., Tsui, V., Crawford, T. D., Audia, J. E., Burdick, D. J., Beresini, M. H., Côté, A., Cummings, R., Duplessis, M., Flynn, E. M., Hewitt, M. C., Huang, H.-R., Jayaram, H., Jiang, Y., Joshi, S., Murray, J., Nasveschuk, C. G., Pardo, E., Poy, F., Romero, F. A., Tang, Y., Taylor, A. M., Wang, J., Xu, Z., Zawadzke, L. E., Zhu, X., Albrecht, B. K., Magnuson, S. R., Bellon, S., and Cochran, A. G. (2018) GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like. J. Med. Chem. 61, 9301-9315. 2. Karim, R. M., Yang, L., Chen, L., Bikowitz, M. J., Lu, J., Grassie, D., Shultz, Z. P., Lopchuk, J. M., Chen, J., and Schonbrunn, E. (2022) Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. J. Med. Chem.65, 4182-4200. 3. Deonarain, M. P., Yahioglu, G., Stamati, I., Saouros, S., and Kapadnis, P. B. (2016) Preparation of drug conjugates and biological materials and their therapeutic uses. Patent: WO2016046574. 4. Phillips, A. J., Nasveschuk, C. G., Henderson, J. A., Liang, Y., Fitzgerald, M. E., and Michael, R. E. (2017) Preparation of bromodomain targeting degronimers for target protein degradation. Patent: WO2017197056. 5. Kanai, M., Kawashima, S., Yamatsugu, K., Zhu, H., Amamoto, Y., Tanabe, K., Ishiguro, T., and Liu, J. (2015) Artificial catalyst system capable of substituting for in vivo acylation function. Patent: WO2015186785. Attorney Docket No.10110-450WO1 6. Zhu, W., Huang, J., Zhang, J., and Xu, W. (2022) Histone deacetylase 8-selective degradation agent, preparation method and application thereof in preparation of antitumor drugs. Patent: CN114409638. 7. Leaver, D. J., Dawson, R. M., White, J. M., Polyzos, A., and Hughes, A. B. (2011) Synthesis of 1,2,3-triazole linked galactopyranosides and evaluation of cholera toxin inhibition. Org. Biomol. Chem.9, 8465-8474. 8. Zhang, J., Che, J., Luo, X., Wu, M., Kan, W., Jin, Y., Wang, H., Pang, A., Li, C., Huang, W., Zeng, S., Zhuang, W., Wu, Y., Xu, Y., Zhou, Y., Li, J., and Dong, X. (2022) Structural Feature Analyzation Strategies toward Discovery of Orally Bioavailable PROTACs of Bruton's Tyrosine Kinase for the Treatment of Lymphoma. J. Med. Chem. 65, 9096-9125. 9. Zang, Y., Qu, Y., Aoki, T., Teraguchi, M., Kaneko, T., Jia, H., Ma, L., and Miao, F. (2019) Simultaneous improvement of permeability and selectivity in enantioselective permeation through solid chiral membranes from a newly synthesized one-handed helical polyphenylacetylene with aldehyde pendant groups by enantioselective reaction. Polymer 171, 45-49. 10. Liu, J., Plewe, M. B., Wang, J., Han, X., and Chen, L. (2020) Preparation of pyrazolopyridines and related heterocycles as CBP and p300 degradation bivalent compds for treatment of diseases. Patent: WO2020173440. Example 2. PROTAC-mediated degradation of TAF1 induces apoptosis in AML cells and inhibits tumor growth in vivo The bromodomain-containing protein TAF1 (TFII-250) is the largest component of the multiprotein assembly TFIID, a dynamic complex that serves as a general factor for transcription initiation. CRISPR and RNAi screens of pan cancer cell lines revealed TAF1 is broadly required for optimal cell growth and survival, but a subset of cell lines showed enhanced TAF1 dependence. These observations suggest that TAF1 has the potential to serve as a therapeutic target in sensitive tumors. Current approaches to target TAF1 are limited to monovalent small molecule inhibitors of the bromodomain. However, recent studies showed that such inhibitors lack cancer cell kill potential. We applied a structure- guided approach to generate cereblon (CRBN) recruiting PROTAC degraders of TAF1 using the chemical scaffolds of ceralasertib and GNE371. We present evidence that GNE371-based PROTACs are effective in degradation of TAF1 at concentrations as low as Attorney Docket No.10110-450WO1 1 nM. TAF1 depletion activated p53 and induced apoptosis in AML cell lines and certain solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenograft. The results showed that inhibition of bromodomain is not sufficient to inactivate TAF1 functions, while a PROTAC approach induces strong biological effects. Furthermore, TAF1 PROTACs have therapeutic potential against AML and other sensitive tumors. Background Transcription is a highly regulated multiple-step process that in eukaryotes starts with the binding of transcription factor IID (TFIID) to gene promoters. TFIID triggers pre- initiation complex (PIC) formation, functions as a coactivator by interacting with transcriptional activators, and recognizes epigenetic marks ^1,2. TFIID is a large multiprotein assembly (> 1 MDa) comprised of the TATA-binding protein (TBP) and up to 14 different TBP-associated factors (TAFs) ^3-5. Notably, undifferentiated human embryonic stem cells contain only six TAFs (TAFs 2, 3, 5, 6, 7 and 11), whereas following differentiation all TAFs are expressed ⁶. Different promoters in human embryonic stem cells are bound by unique subsets of TAFs, resulting in selective expression of genes and maintaining pluripotency ⁶. Recent cryo-electron microscopy studies confirmed the highly dynamic nature of TFIID and the functional significance of its conformational complexity in core promoter recognition and transcription initiation ³. TAF1 (Transcription initiation factor TFIID subunit 1, UniProt ID P21675) is the largest subunit of TFIID and brings other TAFs to promoter regions ^3,7. TAF1 is composed of several domains including a TBP binding domain, a histone acetyltransferase (HAT) domain and a tandem bromodomain (BRD). TAF1 directly interacts with MYC and p53 to regulate MYC-driven gene transcription and p53 mediated G1/S cell cycle transition ^8,9. TAF1 binds to p53 through acetylated lysines to act as a coactivator in transcription regulation, interacts with MDM2 to promote p53 degradation, and phosphorylates p53 at T55 to inhibit DNA binding and promote nuclear export ^9-11. Temperature-sensitive TAF1 mutants caused p53 accumulation and phosphorylation by ATR kinase ^12,13. TAF1 knockdown using siRNA induced p53 accumulation ¹¹. TAF1 was found to be significantly mutated in uterine serous carcinoma, and TAF1 overexpression was described as a major factor for the high mitotic activity in solid tumors ^14,15. Query of the DepMap Portal showed that TAF1 RNAi is modestly growth-inhibitory in most cancer cell lines, while strong dependence was observed in a subset of cell lines. Recently it was demonstrated that TAF1 has a critical role in AML1-ETO driven acute myeloid leukemia (AML) ¹⁶. Knockdown of Attorney Docket No.10110-450WO1 TAF1 impaired the self-renewal and promoted the myeloid differentiation and apoptosis of AML cells. A CRISPR dropout screen also identified TAF1 as an essential gene in several AML cell lines ¹⁷. These observations suggest that pathway rewiring in certain tumors may increase dependency on TAF1, making it a potential therapeutic target in such tumors. To date, TAF1 (and any other TAF) remains an underexplored drug target and no TAF1 inhibitor has reached the clinic. The HAT domain is considered less druggable as it differs from the common architecture found across HAT family members and requires TAF7 for functionality ^18-20. However, the second bromodomain of TAF1 (TAF1-BD2) has been shown to be tractable by small molecule inhibitors. To date, only few bromodomain inhibitors of TAF1 have been reported, specifically the highly selective GNE371 and the less selective BAY-299 ^21,22. Although both inhibitors are potent binders in biochemical assays (Kd 10 nM), effects on cancer cell lines were weak or inconclusive. Targeted PROTAC-induced catalytic protein degradation has provided a paradigm shift in drug discovery and even extends to proteins considered “undruggable” ^23,24. PROTACs have received increasing attention as chemical probes and therapeutics, and over 100 proteins have already been targeted ^25-27. PROTACs are heterobifunctional molecules that incorporate two pharmacophores targeting the protein of interest and recruiting an E3 ubiquitin ligase, mostly cereblon (CRBN) or von Hippel-Lindau (VHL). The resulting ternary complex, Target-PROTAC-E3, facilitates poly-ubiquitination and proteasomal degradation of the target protein. ARV-110, an orally bioavailable PROTAC of the androgen receptor, was the first thalidomide-derived degrader to enter clinical trials ^27-29. Several PROTACs are in clinical trials for cancer and inflammatory diseases, and more are expected to enter clinical trials ^27,30. In this example, we describe the development of potent PROTAC degraders of TAF1 using TAF1 bromodomain inhibitors as warheads for the recruitment of CRBN E3 ligase subunit. The TAF1 PROTACs displayed strong apoptotic activity in AML cells and a subset of solid tumor cells. An in vivo active TAF1 PROTAC inhibited the growth of AML tumor xenograft at tolerable doses, suggesting the approach may provide acceptable therapeutic index for AML and other sensitive tumors. The results provide the foundation to identify tumors with strong dependence on TAF1 and biomarkers that predict TAF1 dependence. Results Degradation of TAF1 by bromodomain targeting PROTACs. Attorney Docket No.10110-450WO1 Given the inactivity of monovalent TAF1 bromodomain inhibitors in cancer cell proliferation and signaling studies, we applied a structure-guided approach towards the development of PROTACs to degrade the TAF1 protein. Recently, we reported the discovery of the ATR kinase inhibitor AZD6738 (ceralasertib) as a bona fide bromodomain inhibitor of TAF1 ³¹. Initial efforts yielded the AZD6738-based PROTACs ZS1-958 and inactive control ZS1-959 (FIG.3A). Based on the encouraging TAF1 degradation activity of ZS1-958, additional PROTACs were synthesized using the high affinity (Kd=1 nM) TAF1 inhibitor GNE371 (ZS3-024, ZS3-025, FIG.3B). Treatment of cancer cells using AZD6738-based PROTACs ZS1-958 and ZS1-998 induced degradation of TAF1 with 6 nM and 0.6 nM DC50 respectively (FIG. 3C). Degradation of TAF1 by ZS1-958 was blocked by monovalent inhibitors AZD6738 and Pomalidomide, TAF1 bromodomain inhibitors GNE371 and BAY299, as well as proteasome inhibitor Bortezomib (FIG. 3D), indicating that it acts through cereblon- mediated proteolysis. Remarkably, AZD6738-based PROTACs were ~200-fold more potent in degrading TAF1 than the binding affinity of free AZD6738 for the TAF1 tandem bromodomain (Kd = 1.7 µM). Additional PROTACs based on the high affinity (Kd=1 nM) TAF1 inhibitor GNE371 (ZS3-024, ZS3-025) were significantly more potent than AZD6738-based PROTACs in AML cells, showing 0.1 nM DC50 in TAF1 degradation (FIG. 3E). TAF1 depletion was complete in <2 hr after treatment with ZS3-025 and was fully recovered 24 hr after drug removal (FIG. 3F). The results indicated that TAF1 can be efficiently targeted through its bromodomain using a PROTAC approach. TAF1 PROTACs induce apoptosis in AML and a subset of solid tumor cells. Tests using a panel of tumor cell lines showed that both AZD6738- and GNE371- based PROTACs induced significant cell death in AML cells (FIG. 4A) and certain solid tumor cells (Saos2, FIG.4A. Table 1). Western blot analysis showed PARP cleavage in cells treated with active PROTAC indicative of apoptosis, whereas methylated control ZS1-959 did not affect TAF1 level or PARP cleavage (FIGs. 4B-4C). TAF1 depletion by shRNA had been shown to cause reduction in the expression of c-Myc ¹⁶. Consistent with this finding, TAF1 depletion by PROTAC also resulted in significant down-regulation of c-Myc (FIG. 4C). A recent CRISPR dropout screen identified TAF1 as an essential gene and a potential target in AML cell lines ¹⁷. Consistent with this report, our tests showed that ZS3- Attorney Docket No.10110-450WO1 025 induced apoptosis in 7/7 AML cell lines and 5/6 lymphoid tumor cell lines independent of p53 status and AML1-ETO fusion (Table 1). Only 3/10 adherent tumor cell lines were apoptotic after TAF1 depletion (Table 1). A recent survey of cell lines showed that CRBN- recruiting PROTAC is more potent in hematopoietic cancer lines compared to solid cancer cells because of higher CRBN expression levels ³². Therefore, CRBN abundance may contribute to the high sensitivity of AML cells to TAF1 PROTACs. Alternatively, hematopoietic tumors may be uniquely dependent on TAF1 for survival. Only a single AML cell line in our test contains the AML1-ETO fusion (Table 1), suggesting that potent TAF1 PROTACs can induce AML cell death independent of AML1-ETO translocation. Table 1. Cell line sensitivity to TAF1 PROTAC induced cell death. Cells were treated with 200 nM ZS1-958 or 50 nM ZS3-025 for 48-96 hr. Apoptosis was determined by morphology and PARP cleavage.

Attorney Docket No.10110-450WO1

Growth inhibition potency of TAF1 PROTAC. The effects of TAF1 PROTAC on cell proliferation and survival was analyzed using MTT assay after 3 days of treatment. The GNE371-based PROTAC ZS3-025 suppressed cell survival with IC50<2 nM for four AML cell lines examined (FIG. 5). Interestingly, Kasumi-1 cells with AML1-ETO fusion did not show higher sensitivity to TAF1 PROTAC compared to cell lines without the fusion (FIG. 5). Solid tumor cell lines (bladder cancer 5637, UC3, HT1375) and normal skin fibroblasts were significantly more resistant to ZS3- 025 (FIG.5). FACS analysis showed ZS3-025 treated AML cell line Molm13 formed debris with sub-2N DNA content characteristic of apoptosis (FIG. 11A). The weak apoptotic 5637 cells and non-apoptotic UC3 cells showed little change in DNA staining profile after ZS3- 025 treatment, suggesting that TAF1 depletion inhibited cell proliferation, but the cells did not arrest at a specific phase of the cell cycle (FIGs.11B-11C). Rescue of PROTAC-induced cell death by non-degradable TAF1-N1583A mutant. Since PROTACs are highly efficient in degrading target proteins, even weak off- target binding may result in cytotoxicity that complicates the interpretation of biological effects. AZD6738 has modest binding affinity for TAF1 and weakly inhibits other bromodomains ³¹. Therefore, AZD6738-based PROTAC is likely to have TAF1-independent cytotoxicity. Consistent with this notion, apoptosis induced by AZD6738-based compound Attorney Docket No.10110-450WO1 ZS1-958 was blocked by monovalent pomalidomide (protects all targets) but not by monovalent GNE371 (protects TAF1), indicating that ZS1-958 has off-target activity sufficient to cause apoptosis independent of TAF1 degradation (FIG. 12A). In contrast, monovalent GNE371 inhibited apoptosis by GNE371-based ZS3-025 (FIG.12B). To further test the specificity of ZS3-025, a rescue experiment was performed to test whether compensatory expression of wt TAF1 or non-degradable TAF1 mutant could block cell death. GNE371 has no effect in most cell lines, suggesting the TAF1 bromodomain is not essential for cell survival ^22,31. Therefore, a TAF1 bromodomain mutant defective for PROTAC binding should be non-degradable and should block apoptosis by specific TAF1 PROTACs. The co-crystal structure of TAF1 bromodomain with GNE371 suggested that residue N1583 is essential for ligand binding ³¹. We generated stable transfected Saos2 cells expressing HA-tagged TAF1-N1583A mutant or wt TAF1. Western blot showed both cell lines were able to sustain low levels of TAF1 protein during treatment with ZS3-025, with HA-TAF1-N1583A contributing more resistance to ZS3-025 than wt HA-TAF1 as expected (FIG.6A). Saos2-HA-TAF1-N1583A cells showed improved survival during treatment with ZS3-025, the cells were able to proliferate at slower rate and reached confluence in the presence of ZS3-025 (FIG. 6B). Saos2-HA-TAF1 cells also showed slightly improved viability, whereas control Saos2-GFP cells were killed by the treatment (FIG. 6B). Western blot of Saos2-HA-TAF1-N1583A and Saos2-HA-TAF1 cells that survived ZS3-025 treatment showed high level HA-TAF1 expression compared to the unchallenged parental pool (FIG. 6C), suggesting the exogenous HA-TAF1 helped the cells to survive ZS3-025 treatment. The results showed that GNE371 PROTAC ZS3-025 induced apoptosis specifically by degrading TAF1. TAF1 depletion by PROTAC activates p53. Previous studies suggested that TAF1 regulates p53 level and activity through several mechanisms: promote MDM2 expression, promote CK1 phosphorylation of MDM2, increase MDM2 stability, promote p53 ubiquitination by MDM2, bind to acetylated p53, phosphorylate p53 Thr55 ^10,11,33-35. Using the potent TAF1 PROTACs, we examined the effect of TAF1 depletion on p53 activity. The results showed that PROTAC treatment of AML cell lines Molm13 and MV-4-11 caused wt p53 accumulation and induction of p21 (FIG. 7A). P53 activation by MDM2 inhibitor Nutlin or DNA damaging drug etoposide led Attorney Docket No.10110-450WO1 to induction of both p21 and MDM2 since both genes are controlled by p53-responsive promoters (FIG. 7A). However, TAF1 PROTACs only induced p21 but not MDM2, consistent with the reported role of TAF1 in maintaining MDM2 promoter activity and protein stability in certain cell lines. TAF1 PROTACs did not induce PUMA, suggesting it may also be needed for PUMA promoter activity (FIG. 7A). The efficiency of p53 activation by TAF1 PROTAC was comparable to MDM2 inhibitor Nutlin, suggesting TAF1 is an important regulator of p53 stability (FIG. 7A). Knockout of p53 in Molm13 cells abrogated p21 induction by ZS3-025, but only slightly reduced apoptosis as indicated by incomplete PARP cleavage after 48 hr treatment (FIG. 7B). MTT assay also corroborated the incomplete cell death at high drug concentrations after p53 knockout (FIG. 7C). The results showed TAF1 depletion led to strong activation of wt p53, which in turn contributed to apoptosis. However, TAF1 depletion has strong p53-independent apoptotic effects. Development of TAF1 PROTAC with in vivo activity. Despite its potent activity in cell culture, ZS3-025 had limited aqueous solubility and did not induce TAF1 depletion in mouse tissues when aqueous formulation was delivered by i.p injection. To address this issue, modifications were introduced into the linker of ZS3-025 to increase rigidity and hydrophilicity (FIG. 8A). The most potent derivative ZS3-046 showed improved solubility and DC50<10 nM in cell culture (FIG. 8B). Treatment of mice with ZS3-046 down-regulated TAF1 in lymphoid tissues in a dose- dependent fashion (FIG. 8C). A single injection of ZS3-046 induced TAF1 down-regulation for >4 days in vivo (FIG. 8D). Treatment of mice bearing subcutaneous HL60 tumor xenografts with ZS3-046 also led to efficient depletion of TAF1 in tumor tissues (FIG.8E). TAF1 PROTAC affects large number of genes. To determine the effect of TAF1 depletion on gene expression, Molm13 cells treated with ZS3-046 for 8 hr were subjected to RNA sequencing (RNA-seq) analysis. The PROTAC treatment altered expression of large number of genes (Fig. 9A). The mRNA levels of 4380 genes (23% of genome) were altered (1590 genes down-regulated by 2-16 fold, 2790 genes induced by 2-64 fold). Gene set enrichment analysis showed 41 pathways were significantly affected by ZS3-046 treatment ³⁶. Down-regulation of large number of genes after TAF1 depletion was consistent with its function as an important subunit of the transcription initiation complex. It is noteworthy that there were more activated genes than suppressed genes after TAF1 depletion, presumably due to TAF1 depletion upregulating other Attorney Docket No.10110-450WO1 transcription activators including p53. TAF1 PROTAC induced wt p53 accumulation in Molm13 cells (FIGs. 7A-7C), but the unbiased gene set enrichment analysis did not flag p53 pathway as being specifically affected. Comparison of ZS3-046 regulated genes to a list of 343 p53 target genes (curated from multiple cell lines and cell types) showed 37 p53 targets (including CDKN1A that encodes p21) were induced and 23 were down-regulated by ZS3-046 in Molm13 cells ³⁷. The effects of TAF1 depletion on p53 target genes is consistent with the complex roles of TAF1 in promoting p53 degradation while also acting as a co-activator of p53-mediated transcription. Global proteomic profiling of TAF1 PROTAC. The specificity of ZS3-046 was investigated using tandem mass tag quantitative analysis. HL60 cells were treated for 6 hours with 100 nM compound, inactive compound ZS3-061 with methylated pomalidomide (FIG. 8A) served as control. The assay detected 7135 proteins but did not detect TAF1 in control samples even after targeted search. A survey of unrelated data sets showed TAF1 was not detectable in most tandem mass tag analyses, possibly due to low abundance. Therefore, TAF1 depletion was verified by western blot (FIG. 9B). The proteomic analysis results showed ZS3-046 induced >2 fold decrease of 6 proteins (FIGs.9C-D). The proteomics volcano plot showed an asymmetric pattern for ZS3-046, down- regulated proteins showed wider spread of log2 fold change compared to up-regulated proteins (FIG. 9C). Comparison of the proteomics and RNA-seq data showed that 64% of down-regulated proteins had decreased mRNA expression, suggesting mRNA down- regulation due to TAF1 depletion may cause the decrease of certain proteins. Therefore, the log2Foldchange values of top-ranked proteomics hits were normalized using corresponding mRNA log2Foldchange results (with the caveat that protein and mRNA data were from different AML cell lines). The normalized data showed only 1 protein (MIER1) was down- regulated ~2 fold by ZS3-046 (FIG. 9D). The results suggest ZS3-046 is highly specific in protein degradation. Toxicity of TAF1 PROTAC in vivo. TAF1 is a general transcription factor and is flagged as a common essential gene in the DepMap portal, showing significant growth inhibition of most cancer cell lines after CRISPR targeting. The effect of TAF1 depletion on normal tissues was examined in mice. Repeated administration of ZS3-046 at 20 mg/kg exceeded maximal tolerability (FIG.10A), Attorney Docket No.10110-450WO1 inducing cell death and pathological changes in multiple tissues (FIG. 10B). Doses of 10 mg/kg and 5 mg/kg were well tolerated with no significant weight change or signs of toxicity. The tolerable doses of ZS3-046 induced sub-maximal but significant reduction of TAF1 level in mouse tissues (FIG.8C), suggesting that short-term partial depletion of TAF1 in normal tissues was tolerated. TAF1 PROTAC induces tumor regression. To determine whether TAF1 PROTAC treatment at tolerable doses can produce therapeutic effects, nude mice bearing established HL60 subcutaneous tumor xenografts (50-200 mg) were treated with 4-5 injections of ZS3-046 at 10 mg/kg or 5 mg/kg per injection in a 14-day span. The treatments resulted in significant inhibition of tumor growth, whereas vehicle treated tumors rapidly progressed to end point (FIG. 10C). The treatment did not cause visible signs of toxicity or weight loss (FIG. 10D). The results showed ZS3- 046 has anti-tumor activity in vivo at acceptable doses, suggesting TAF1 PROTACs have therapeutic potential against certain AML tumor types. Discussion Previous approaches to target TAF1 were limited to identifying monovalent inhibitors of its bromodomains. Our own data along with previously reported observations support the notion that such inhibitors lack anti-cancer properties ³¹. TAF1 is a large protein of 1892 amino acids containing two potential kinase domains, a HAT domain and two bromodomains. The weak biological phenotype of TAF1 bromodomain inhibitors suggests cells can survive with minimal residual activity from this domain. In contrast, our TAF1 PROTACs derived from monovalent inhibitors showed remarkable biological activities. Key observations include: (1) potent and complete degradation of TAF1 in blood and solid cancer cells; (2) induction of apoptosis and cell killing occurs only in certain cell lines, particularly AML; (3) degradation activity is up to 100 times higher than binding affinity for TAF1 (i.e., catalytic mechanism of action); (4) treated cells can be rescued by monovalent inhibitors or non-degradable TAF1 mutant expression indicating on-target activity; (5) low doses significantly inhibit AML tumor xenograft growth and are compatible with long-term survival of mice. Our data suggest that degradation of TAF1 is a viable strategy to selectively target cancers such as AML with high dependence on TAF1 and expressing elevated levels of CRBN. Attorney Docket No.10110-450WO1 Development of potent TAF1 PROTACs provided new evidence on the role of TAF1 as an important regulator of p53 stability and activity. They also facilitated analysis of TAF1 contribution to global gene expression. Down-regulation of large number of genes (n=1590) after TAF1 depletion was consistent with its function as a central subunit of the TFIID transcription initiation complex. However, these genes only account for 8.5% of the transcriptome, suggesting that transcription of most genes are TAF1-independent or can be sustained with very low TAF1 level. It is also noteworthy that there were more activated genes (n=2790) than suppressed genes 8 hours after TAF1 depletion was initiated, suggesting TAF1 may have a novel role in transcription repression. Alternatively, widespread gene activation may be an indirect effect of TAF1 regulating other transcription activators as illustrated by its complex effects on p53 degradation and transcription activity. The potent PROTACs described in this example will provide valuable chemical probes for further investigating TAF1 biological functions. In a previous study a cIAP-dependent PROTAC targeting RIPK2 induced target depletion for up to 7 days in rats after administrating a single dose ³⁸. Our analysis of CRBN-dependent ZS3-046 in mice showed TAF1 depletion was sustained for >4 days after a single dose. Tumor control was achieved by administering the PROTAC in 5-day intervals. This observation demonstrates the unique ability of PROTACs in inducing prolonged target depletion due to catalytic mechanism and high potency. Although this feature may be advantageous in treating diseases that prefer sustained target inhibition, it may not be optimal for cancer treatment where there is a need to control toxicity to normal tissues. It is possible that complete depletion of TAF1 for a short period of time is sufficient for tumor cell kill while reducing toxicity to normal tissues. The long action of ZS3-046 prevents the testing of such dosing scheme. This issue can be addressed in future studies by modulating the stability and in vivo activity of TAF1 PROTACs. Development of effective cancer therapeutics involves selection of targets with high tumor dependency or achieving tumor-specific inhibition. This example shows that TAF1 is druggable using a PROTAC approach, producing strong anti-tumor effects, but has toxicity that requires careful management. TAF1 dropout analysis in ~1000 cancer cell lines showed it is a common essential gene with a wide range of dependency. Consistent with this finding, our TAF1 PROTAC showed modest effect on certain cancer cell lines despite target depletion, while inducing potent cell death in AML and lymphoma cell lines. In vivo tests showed that extended treatment with TAF1 PROTAC resulted in toxicity to multiple organs Attorney Docket No.10110-450WO1 that could be dose-limiting when treating tumors with low TAF1 dependency. The ability to identify a therapeutic window for AML tumor model underscores the importance of focusing on sensitive tumor types and dose optimization to minimize toxicity when targeting a common essential gene. Materials and methods Plasmids and cell lines. Adherent solid tumor cell lines were maintained in Dulbecco modified Eagle medium (DMEM) with 10% fetal bovine serum. Non-adherent tumor cell lines were maintained in RPMI medium with 10% fetal bovine serum. All cell lines used in this example were originally obtained from the ATCC and authenticated and tested negative for mycoplasma contamination. Molm13 cells with p53 knockout were generated by infection with lentivirus (LentiCRISPRv2 vector, Addgene #52961) containing p53gRNA3 and selection with puromycin to obtain pooled transduced cells. Saos2 cells with stable expression of exogenous TAF1 were generated by cotransfection of CMV-driven HA-TAF1 plasmid (Addgene #17997 for TAF1 wt. Site-directed mutagenesis was performed to create TAF1-N1583A mutant.) with pBabe-Puro plasmid, followed by puromycin selection for transfected pools. Western blot and protein interaction analysis. Cultured cells were lysed in RIPA buffer (50 mM Tris–HCl pH 7.4, 150 mM NaCl, 1% Triton-X100, 0.1% SDS, 1% sodium deoxycholate, 2x protease inhibitor cocktail). Lysate was sonicated for 10 cycle (30 sec on and 30 sec off) and centrifuged for 10 minutes at 14,000 x g at 4ûC, and the insoluble debris was discarded. Mouse tissues snap frozen in liquid nitrogen and stored at -80ûC were homogenized in RIPA buffer (50 mM Tris–HCl pH 7.4, 150 mM NaCl, 1% Triton-X100, 0.1% SDS, 1% sodium deoxycholate, 2x protease inhibitor cocktail) and centrifuged for 10 minutes at 14,000 x g at 4ûC, and the insoluble debris was discarded. Cell lysate (10–50 µg of protein determined by Pierce BCA protein assay reagent) was fractionated by SDS–PAGE and transferred to Immobilion P filters (Millipore). The filter was blocked for 1 hr with phosphate buffered saline (PBS) containing 5% non-fat dry milk and 0.1% Tween 20, incubated with primary and secondary antibodies, and the filter was developed using Supersignal west pico plus chemiluminescent substrate (Thermo Fisher). MDM2 was detected using monoclonal antibody 3G9 produced in house. Other markers were detected using commercial antibodies: Actin (Sigma A5441), Attorney Docket No.10110-450WO1 p53-DO1 (BD Biosciences 554293), p21 (BD Biosciences 556430), TAF1 (Cell Signaling Technology 12781S), PARP (BD Biosciences 556362), c-Myc (ATCC MYC1-9E10.2), PUMA (Cell Signaling Technology 12450S). Cell viability assay. Cell lines were seeded in 96-well plates and treated with PROTAC compounds at indicated concentrations for 3 days. CellTiter 96 AQueous One Solution reagent (ThermoFisher #PR-G3580) was added to final ratio of 4% (V/V). The plates were incubated at 37ûC for 1-3 hr and OD490 was measured as readout of viable cells. Each experiment includes 3 biological replicates. The results were presented as mean ± standard deviation (SD). Experiments were performed at least 2 times. RNA Sequencing (RNA-seq). Molm13 cells were treated with 100 nM ZS3-046 for 8 hr in triplicate. Total RNA samples were prepared using RNeasy min kit (Qiagen). RNA-seq analysis including rRNA depletion, library preparation, multiplexing and cluster generation, sequencing on Illumina HiSeq2500, and differential gene expression initial analysis, were performed by Genewiz (South Plainfield, NJ, USA). Proteomics profiling. HL60 cells were treated with active PROTAC ZS3-046 and inactive control compound ZS3-061 at 100 nM for 6 hr in triplicate. The cells were harvested, flash frozen in liquid nitrogen, and stored at -80ûC. The samples were analyzed as part of a 18-plex tandem mass tag experiment. Cells were lysed in denaturing lysis buffer containing 8M urea, 20 mM HEPES (pH 8), 1 mM sodium orthovanadate, 2.5 mM sodium pyrophosphate and 1 mM -glycerophosphate. A Bradford assay was carried out to determine the protein concentration. The proteins were reduced with 4.5 mM DTT and alkylated with 10 mM iodoacetamide. Trypsin digestion was carried out at room temperature overnight, and tryptic peptides were then acidified with 1% trifluoroacetic acid (TFA) and desalted with C18 Sep- Pak cartridges according to the manufacturer’s procedure. Peptide from each sample was labeled with TMTPro18plex reagent. The label incorporation was checked by LC-MS/MS and spectral counting. 95% or greater label incorporation was achieved for each channel. The samples were then pooled and lyophilized. After lyophilization, the peptides were re- dissolved in 400 micro liter of 20 mM Ammonium Formate, (pH 10.0). The high pH reversed phase separation was performed on a Xbridge 4.6 mm x 100 mm column packed Attorney Docket No.10110-450WO1 with BEH C18 resin, 3.5 µm, 130Å (Waters). The peptides were eluted as follows: 5% B (5 mM Ammonium Formate, 90% acetonitrile, pH 10.0) for 10 minutes, 5%-15% B in 5 minutes, 15-40% B in 47 minutes, 40-100% B in 5 minutes and 100% B held for 10 minutes, followed by re-equilibration at 1% B. The flow rate was 0.6 ml/min, and 12 concatenated fractions were collected. Speedvac centrifuge was used to dry the peptides. A nanoflow ultra high performance liquid chromatograph (RSLC, Dionex, Sunnyvale, CA) coupled to an electrospray bench top orbitrap mass spectrometer (Orbitrap Exploris480 with FAIMS, Thermo, San Jose, CA) was used for tandem mass spectrometry peptide sequencing experiments. The sample was first loaded onto a pre-column (2 cm x 100 µm ID packed with C18 reversed-phase resin, 5µm, 100Å) and washed for 8 minutes with aqueous 2% acetonitrile and 0.04% trifluoroacetic acid. The trapped peptides were eluted onto the analytical column (C18, 75 µm ID x 25 cm, 2 µm, 100Å, Dionex, Sunnyvale, CA). The 120-minute gradient was programmed as: 95% solvent A (2% acetonitrile + 0.1% formic acid) for 8 minutes, solvent B (90% acetonitrile + 0.1% formic acid) from 5% to 38.5% in 90 minutes, then solvent B from 50% to 90% B in 7 minutes and held at 90% for 5 minutes, followed by solvent B from 90% to 5% in 1 minute and re-equilibrate for 10 minutes. The flow rate on analytical column was 300 nl/min. Two CV values (-45 and -65) were used with 1.5 second cycle time each for data dependent acquisition. Spray voltage was 2100v and capillary temperature was 300 °C. The resolution for MS and MS/MS scans were set at 120,000 and 45,000 respectively. Dynamic exclusion was 15 seconds for previously sampled peptide peaks. MaxQuant (version 1.6.14.0) was used to identify peptides and quantify the TMT reporter ion intensities. Up to 2 missed trypsin cleavages were allowed. The mass tolerance was 20 ppm first search and 4.5 ppm main search. Reporter ion mass tolerance was set to 0.003 Da. Minimal Precursor intensity fraction 0.75. Carbamidomethyl cysteine was set as fixed modification. Both peptide spectral match (PSM) and protein false discovery rate (FDR) were set at 0.01. Match between runs feature was activated to carry identifications across samples. For data upload to PRIDE/ProteomeXchange, similar database searches were performed with Mascot (www.matrixscience.com) in Proteome Discoverer (Thermo). Animal experiment. ZS3-046 was dissolved in 50% 2-hydroxypropyl-^-cyclodextrin (HBC) solution (w/v in H2O), followed by addition of equal volume PBS buffer to prepare a 5 mg/ml stock solution containing 25% HBC for storage at -80ûC. The stock solution was diluted using Attorney Docket No.10110-450WO1 PBS to reach the required dosage and volume (0.1 ml/mouse) for intraperitoneal injection. Animal experiments were reviewed and approved by the University of South Florida IACUC. Athymic female nude mice (6-week old, Athymic Nude-Foxn1nu, Envigo) were injected subcutaneously with 0.1 ml 1:1 slurry of Matrigel (VWR 47743-715) and 1x10⁷ HL60 cells in PBS at each site. When tumors reached average size of ~200 mg the mice were randomized into groups and treated with vehicle or PROTAC once every 4-5 days. Tumor growth was measured using a digital caliper and volume was calculated with the formula 0.5xLxW². Statistical analysis. The experimental results were presented as the mean ± standard deviation (SD), and _{Student's t test was used to evaluate differences between groups. P < 0.05 was considered} statistically significant. References for Example 2 1. Papai, G., Tripathi, M. K., Ruhlmann, C., Layer, J. H., Weil, P. A. & Schultz, P. TFIIA and the transactivator Rap1 cooperate to commit TFIID for transcription initiation. Nature 465, 956-960 (2010). 2. Muller, F., Zaucker, A. & Tora, L. Developmental regulation of transcription initiation: more than just changing the actors. Curr Opin Genet Dev 20, 533-540 (2010). 3. Patel, A. B., Greber, B. J. & Nogales, E. Recent insights into the structure of TFIID, its assembly, and its binding to core promoter. Curr Opin Struct Biol 61, 17-24 (2020). 4. Bieniossek, C., Papai, G., Schaffitzel, C., Garzoni, F., Chaillet, M., Scheer, E., Papadopoulos, P., Tora, L., Schultz, P. & Berger, I. The architecture of human general transcription factor TFIID core complex. Nature 493, 699-702 (2013). 5. Burley, S. K. & Roeder, R. G. Biochemistry and structural biology of transcription factor IID (TFIID). Annu Rev Biochem 65, 769-799 (1996). 6. Maston, G. A., Zhu, L. J., Chamberlain, L., Lin, L., Fang, M. & Green, M. R. Non- canonical TAF complexes regulate active promoters in human embryonic stem cells. Elife 1, e00068 (2012). 7. Patel, A. B., Louder, R. K., Greber, B. J., Grunberg, S., Luo, J., Fang, J., Liu, Y., Ranish, J., Hahn, S. & Nogales, E. Structure of human TFIID and mechanism of TBP loading onto promoter DNA. Science 362 (2018). Attorney Docket No.10110-450WO1 8. Wei, Y., Resetca, D., Li, Z., Johansson-Akhe, I., Ahlner, A., Helander, S., Wallenhammar, A., Morad, V., Raught, B., Wallner, B., Kokubo, T., Tong, Y., Penn, L. Z. & Sunnerhagen, M. Multiple direct interactions of TBP with the MYC oncoprotein. Nat Struct Mol Biol 26, 1035-1043 (2019). 9. Cai, X. & Liu, X. Inhibition of Thr-55 phosphorylation restores p53 nuclear localization and sensitizes cancer cells to DNA damage. Proc Natl Acad Sci U S A 105, 16958-16963 (2008). 10. Li, A. G., Piluso, L. G., Cai, X., Gadd, B. J., Ladurner, A. G. & Liu, X. An acetylation switch in p53 mediates holo-TFIID recruitment. Mol Cell 28, 408-421 (2007). 11. Allende-Vega, N., Saville, M. K. & Meek, D. W. Transcription factor TAFII250 promotes Mdm2-dependent turnover of p53. Oncogene 26, 4234-4242 (2007). 12. Wasylyk, C. & Wasylyk, B. Defect in the p53-Mdm2 autoregulatory loop resulting from inactivation of TAF(II)250 in cell cycle mutant tsBN462 cells. Mol Cell Biol 20, 5554- 5570 (2000). 13. Buchmann, A. M., Skaar, J. R. & DeCaprio, J. A. Activation of a DNA damage checkpoint response in a TAF1-defective cell line. Mol Cell Biol 24, 5332-5339 (2004). 14. Hong, B., Le Gallo, M. & Bell, D. W. The mutational landscape of endometrial cancer. Curr Opin Genet Dev 30, 25-31 (2015). 15. Wada, C., Kasai, K., Kameya, T. & Ohtani, H. A general transcription initiation factor, human transcription factor IID, overexpressed in human lung and breast carcinoma and rapidly induced with serum stimulation. Cancer Res 52, 307-313 (1992). 16. Xu, Y., Man, N., Karl, D., Martinez, C., Liu, F., Sun, J., Martinez, C. J., Martin, G. M., Beckedorff, F., Lai, F., Yue, J., Roisman, A., Greenblatt, S., Duffort, S., Wang, L., Sun, X., Figueroa, M., Shiekhattar, R. & Nimer, S. TAF1 plays a critical role in AML1-ETO driven leukemogenesis. Nat Commun 10, 4925 (2019). 17. Tzelepis, K., Koike-Yusa, H., De Braekeleer, E., Li, Y., Metzakopian, E., Dovey, O. M., Mupo, A., Grinkevich, V., Li, M., Mazan, M., Gozdecka, M., Ohnishi, S., Cooper, J., Patel, M., McKerrell, T., Chen, B., Domingues, A. F., Gallipoli, P., Teichmann, S., Ponstingl, H., McDermott, U., Saez-Rodriguez, J., Huntly, B. J. P., Iorio, F., Pina, C., Vassiliou, G. S. & Yusa, K. A CRISPR Dropout Screen Identifies Genetic Vulnerabilities and Therapeutic Targets in Acute Myeloid Leukemia. Cell Rep 17, 1193-1205 (2016). Attorney Docket No.10110-450WO1 18. Bhattacharya, S., Lou, X., Hwang, P., Rajashankar, K. R., Wang, X., Gustafsson, J. A., Fletterick, R. J., Jacobson, R. H. & Webb, P. Structural and functional insight into TAF1-TAF7, a subcomplex of transcription factor II D. Proc Natl Acad Sci U S A 111, 9103- 9108 (2014). 19. Wang, H., Curran, E. C., Hinds, T. R., Wang, E. H. & Zheng, N. Crystal structure of a TAF1-TAF7 complex in human transcription factor IID reveals a promoter binding module. Cell Res 24, 1433-1444 (2014). 20. Nogales, E., Patel, A. B. & Louder, R. K. Towards a mechanistic understanding of core promoter recognition from cryo-EM studies of human TFIID. Curr Opin Struct Biol 47, 60-66 (2017). 21. Bouche, L., Christ, C. D., Siegel, S., Fernandez-Montalvan, A. E., Holton, S. J., Fedorov, O., Ter Laak, A., Sugawara, T., Stockigt, D., Tallant, C., Bennett, J., Monteiro, O., Diaz-Saez, L., Siejka, P., Meier, J., Putter, V., Weiske, J., Muller, S., Huber, K. V. M., Hartung, I. V. & Haendler, B. Benzoisoquinolinediones as potent and selective inhibitors of BRPF2 and TAF1/TAF1L bromodomains. J Med Chem 60, 4002-4022 (2017). 22. Wang, S., Tsui, V., Crawford, T. D., Audia, J. E., Burdick, D. J., Beresini, M. H., Cote, A., Cummings, R., Duplessis, M., Flynn, E. M., Hewitt, M. C., Huang, H. R., Jayaram, H., Jiang, Y., Joshi, S., Murray, J., Nasveschuk, C. G., Pardo, E., Poy, F., Romero, F. A., Tang, Y., Taylor, A. M., Wang, J., Xu, Z., Zawadzke, L. E., Zhu, X., Albrecht, B. K., Magnuson, S. R., Bellon, S. & Cochran, A. G. GNE-371, a Potent and Selective Chemical Probe for the Second Bromodomains of Human Transcription-Initiation-Factor TFIID Subunit 1 and Transcription-Initiation-Factor TFIID Subunit 1-like. J Med Chem 61, 9301- 9315 (2018). 23. Churcher, I. Protac-Induced Protein Degradation in Drug Discovery: Breaking the Rules or Just Making New Ones? J Med Chem 61, 444-452 (2018). 24. Ishida, T. & Ciulli, A. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones. SLAS Discov 26, 484-502 (2021). 25. Burslem, G. M. & Crews, C. M. Proteolysis-Targeting Chimeras as Therapeutics and Tools for Biological Discovery. Cell 181, 102-114 (2020). 26. Kostic, M. & Jones, L. H. Critical Assessment of Targeted Protein Degradation as a Research Tool and Pharmacological Modality. Trends Pharmacol Sci 41, 305-317 (2020). Attorney Docket No.10110-450WO1 27. Mullard, A. Targeted protein degraders crowd into the clinic. Nat Rev Drug Discov 20, 247-250 (2021). 28. Bond, M. J. & Crews, C. M. Proteolysis targeting chimeras (PROTACs) come of age: entering the third decade of targeted protein degradation. RSC Chem Biol 2, 725-742 (2021). 29. Pike, A., Williamson, B., Harlfinger, S., Martin, S. & McGinnity, D. F. Optimising proteolysis-targeting chimeras (PROTACs) for oral drug delivery: a drug metabolism and pharmacokinetics perspective. Drug Discov Today 25, 1793-1800 (2020). 30. O'Brien Laramy, M. N., Luthra, S., Brown, M. F. & Bartlett, D. W. Delivering on the promise of protein degraders. Nat Rev Drug Discov 22, 410-427 (2023). 31. Karim, R. M., Yang, L., Chen, L., Bikowitz, M. J., Lu, J., Grassie, D., Shultz, Z. P., Lopchuk, J. M., Chen, J. & Schonbrunn, E. Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. J Med Chem 65, 4182-4200 (2022). ^{32. Luo, X., Archibeque, I., Dellamaggiore, K., Smither, K., Homann, O., Lipford, J. R.} & Mohl, D. Profiling of diverse tumor types establishes the broad utility of VHL-based ProTaCs and triages candidate ubiquitin ligases. iScience 25, 103985 (2022). 33. Li, H. H., Li, A. G., Sheppard, H. M. & Liu, X. Phosphorylation on Thr-55 by TAF1 mediates degradation of p53: a role for TAF1 in cell G1 progression. Mol Cell 13, 867-878 (2004). 34. Allende-Vega, N., McKenzie, L. & Meek, D. Transcription factor TAFII250 phosphorylates the acidic domain of Mdm2 through recruitment of protein kinase CK2. Mol Cell Biochem 316, 99-106 (2008). 35. Wu, Y., Lin, J. C., Piluso, L. G., Dhahbi, J. M., Bobadilla, S., Spindler, S. R. & Liu, X. Phosphorylation of p53 by TAF1 inactivates p53-dependent transcription in the DNA damage response. Mol Cell 53, 63-74 (2014). 36. Hanzelmann, S., Castelo, R. & Guinney, J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14, 7 (2013). 37. Fischer, M. Census and evaluation of p53 target genes. Oncogene 36, 3943-3956 (2017). Attorney Docket No.10110-450WO1 38. Mares, A., Miah, A. H., Smith, I. E. D., Rackham, M., Thawani, A. R., Cryan, J., Haile, P. A., Votta, B. J., Beal, A. M., Capriotti, C., Reilly, M. A., Fisher, D. T., Zinn, N., Bantscheff, M., MacDonald, T. T., Vossenkamper, A., Dace, P., Churcher, I., Benowitz, A. B., Watt, G., Denyer, J., Scott-Stevens, P. & Harling, J. D. Extended pharmacodynamic responses observed upon PROTAC-mediated degradation of RIPK2. Commun Biol 3, 140 (2020). Additional Experimental Details for Example 2 Synthetic Chemistry Procedures Reagents were purchased at the highest commercial quality and used without further purification unless otherwise stated. All solvents were passed through an activated alumina column (PPT Glass Contour Solvent Purification System) followed by drying over molecular sieves (3Å or 4 Å) and kept under an Argon balloon. Reactions performed at room temperature varied from 21–23 ºC. Yields refer to chromatographically and spectroscopically (¹H NMR) homogeneous material, unless otherwise stated. Purifications were performed via column chromatography manually using SiliCycle SiliaFlash^® P60 (particle size 40–63 m) silica gel, or on a Biotage^® Isolera One, unless otherwise stated. Reactions were monitored by Thin Layer Chromatography (TLC) carried out on 250 mm SiliCycle SiliaPlates (TLC Glass-Backed TLC Extra Hard Layer, 60Å) or Liquid Chromatography Mass Spectrometry (LC–MS). Plates were visualized using short range UV light, I2, KMnO4, or CAM. NMR spectra were recorded on a Bruker Ascend^TM 500 MHz instrument and were calibrated using residual non-deuterated solvent as an internal reference (CDCl3: 7.26 ppm ¹H NMR, 77.16 ppm ¹³C NMR). The following abbreviations were used to explain NMR peak multiplicities: app. = apparent, s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = heptet, dd = doublet of doublet, dt = doublet of triplet, pd = pentet of doublet, dq = doublet of quartet, td = triplet of doublet, dtd = doublet of triplet of doublet, ddd = doublet of doublet of doublet, ddt = doublet of doublet of triplet, ddq = doublet of doublet of quartet, m = multiplet. NMR multiplicities (J-values) were determined using MestReNova processing software with Global Spectral Deconvolution (GSD). High- resolution mass spectra (HRMS) were recorded on an Agilent 6230 LC–MS TOF mass spectrometer using electrospray ionization time-of-flight (ESI-TOF). Compound purity was determined using a Agilent 1260 Infinity series HPLC system with ZORBAX RX-SIL 4.6 mm ID x 150 mm (5 µm) column using acetonitrile/water (0.1% formic acid) solvent system. Attorney Docket No.10110-450WO1

TAF1 ligands used for PROTAC development. The TAF1 ligands used within this example, ceralasertib (AZD6738) and GNE371, were prepared from our previously reported procedures. ^1-2 Syntheses of linkers and E3 ligase ligands used in this example were performed based on previous reports with modifications in some instances; their use for the preparation of TAF1 PROTACs are described below. Synthesis of linkers and E3 ligase ligands:

Synthesis of 1-azido-8-bromooctane (S2). 1-azido-8-bromooctane (S2) was prepared according to a previous report.³ In a 20 mL vial equipped with a stir bar was 1,8-dibromooctane (S1) (2.94 g, 10.8 mmol, 2 eq.) in DMF (8.5 mL) at room temperature. NaN3 (351 mg, 5.40 mmol, 1 eq.) was added and the reaction was heated to 50 C for 18 hours. The reaction mixture was cool to room temperature, diluted with hexanes (100 mL), washed with water (2 x 50 mL) and brine (50 mL), dried over Na²SO⁴, filtered and concentrated. Further purification by silica gel column chromatography using hexanes/EtOAc (0% to 2% EtOAc) provided 10 (1.14 g, 4.87 mmol, 90% yield) as a clear colorless oil. TLC: Rf = 0.26 (100% hexanes, PMA stain). ¹H NMR: (500 MHz, CDCl3) 3.40 (t, J = 6.8 Hz, 2H), 3.26 (t, J = 6.9 Hz, 2H), 1.90 – 1.81 (m, 2H), 1.63 – 1.56 (m, 2H), 1.48 – 1.40 (m, 2H), 1.40 – 1.29 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 51.5, 33.9, 32.8, 29.0, 28.8, 28.6, 28.1, 26.6 ppm. Attorney Docket No.10110-450WO1 Synthesis of 7-bromoheptanal (S4). 7-bromoheptanal (S4) was prepared according to a previous report.⁴ In a 100 mL round-bottomed flask equipped with a stir bar and opened to air, 1 (2.15 g, 11.0 mmol, 1 eq.), DCM (23 mL), and TEMPO (17.2 mg, 110 mol, 0.01 eq.) were added. An aqueous solution of NaOCl (22 mL, 15.4 mmol, 1.4 eq., 5%; prepared by mixing an 11% aqueous stock solution of NaOCl (10 mL) and a saturated aqueous solution of NaHCO3 (12 mL)) was added and vigorously stirred at room temperature for 1 hour. Upon completion (TLC: 20% EtOAc/Hex) the reaction was quenched with saturated aqueous Na2S2O3 (30 mL), aqueous layer extracted using DCM (4 x 50 mL), combined organic layers were washed with saturated aqueous NaHCO3 (2 x 40 mL), brine (40 mL), then dried over Na²SO⁴, filtered and concentrated to give S4 (2.09 g, 10.8 mmol, 98% yield) as an amber liquid that was sufficiently pure by NMR and used in the next step without further purification. TLC: Rf = 0.80 (20% EtOAc in hexanes UV). ¹H NMR: (500 MHz, CDCl3) 9.77 (t, J = 1.7 Hz, 1H), 3.41 (t, J = 6.8 Hz, 2H), 2.45 (td, J = 7.2, 1.6 Hz, 2H), 1.91 – 1.82 (m, 2H), 1.72 – 1.60 (m, 2H), 1.51 – 1.43 (m, 2H), 1.41 – 1.33 (m, 2H) ppm. ¹³C NMR: (126 MHz, CDCl3) 202.5, 43.7, 33.7, 32.5, 28.3, 27.9, 21.8 ppm.

Synthesis of 2-(6-bromohexyl)-1,3-dioxolane (S5). 2-(6-bromohexyl)-1,3-dioxolane (S5) was prepared according to previous reports.^4-5 In a 50 mL round-bottomed flask equipped with a stir bar, 7-bromoheptanal (S4) (908 mg, 4.70 mmol, 1 eq.), toluene (23 mL), ethylene glycol (584 mg, 9.41 mmol, 2 eq.), and p- _{TsOH H2O (45.0 mg, 235 mol, 0.05 eq.) were added sequentially. The flask was equipped} with a Dean-stark trap and reflux condenser then heated to 110 ºC for 18 hours. The reaction was cooled to room temperature, diluted with Et2O (60 mL), organic layer washed with saturated aqueous NaHCO3 (2 x 25 mL) then water (2 x 25 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using hexanes/Et2O (0% to 20% Et2O) provided 2-(6-bromohexyl)-1,3- dioxolane (S5) (722 mg, 3.04 mmol, 65% yield) as a clear colorless oil. TLC: Rf = 0.71 (10% EtOAc in hexanes UV).¹H NMR: (500 MHz, CDCl3) 4.84 (t, J = 4.7 Hz, 1H), 4.01 Attorney Docket No.10110-450WO1 – 3.91 (m, 2H), 3.88 – 3.81 (m, 2H), 3.40 (t, J = 6.8 Hz, 2H), 1.89 – 1.82 (m, 2H), 1.68 – 1.62 (m, 2H), 1.49 – 1.40 (m, 4H), 1.39 – 1.33 (m, 2H) ppm.¹³C NMR: (126 MHz, CDCl3) 104.5, 64.9, 33.9, 33.8, 32.7, 28.7, 28.1, 23.8 ppm.

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (S8). 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindoline-1,3-dione (S8) was prepared according to a previous report.⁶ In a 200 mL round-bottomed flask equipped with a stir bar and reflux condenser was S6 (3.05 g, 18.4 mmol, 1 eq.) and S7 (3.32 g, 20.2 mmol, 1.1 eq) in AcOH (30 mL) at room temperature. KOAc (5.41 g, 55.1 mmol, 3 eq.) was added and the reaction mixture was heated to 125 C for 18 hours. The mixture was cooled to room temperature and AcOH was removed under reduced pressure. H2O (200 mL) was added, and the resulting suspension stirred at room temperature for 2 hours. The solid was filtered and washed with H2O (250 mL) and dried to give S8 (4.59 g, 16.6 mmol, 90 % yield) as a light-grey solid. ¹H NMR: (500 MHz, DMSO) 11.14 (s, 1H), 7.94 (td, J = 7.9, 4.5 Hz, 1H), 7.78 (d, J = 7.3 Hz, 1H), 7.72 (t, J = 8.9 Hz, 1H), 5.15 (dd, J = 12.9, 5.4 Hz, 1H), 2.88 (ddd, J = 17.5, 14.1, 5.4 Hz, 1H), 2.60 (d, J = 17.5 Hz, 1H), 2.56 – 2.45 (m, 1H), 2.12 – 2.01 (m, 1H) ppm. ¹⁹F NMR: (471 MHz, DMSO) -114.66 ppm.¹³C NMR: (126 MHz, DMSO) 173.2, 170.2, 166.6 (d, J = 2.6 Hz), 164.4, 157.3 (d, J = 262.3 Hz), 138.5 (d, J = 7.9 Hz), 133.9, 123.5 (d, J = 19.6 Hz), 120.5 (d, J = 3.0 Hz), 117.5 (d, J = 12.6 Hz), 49.6, 31.4, 22.3 ppm.

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (S10). 2-(2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-ylamino)isoindoline-1,3-dione (S10) was prepared according to previous reports.^7-8 Attorney Docket No.10110-450WO1 In a 20 mL septum-capped reaction vial equipped with a stir bar was S8 (550 mg, 2.01 mmol, 1 eq.) and S9 (122 mg, 142 L, 2.21 mmol, 1.1 eq.) in DMA (8 mL) at room temperature. DIPEA (1.05 mL, 6.03 mmol, 3 eq.) was added and the reaction mixture was heated to 90 C for 19.5 hours. The mixture was cooled to room temperature then quenched with saturated aqueous NH4Cl (20 mL) and extracted with EtOAc (3 x 35 mL). The combined organic layers were washed with brine (3 x 15 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using hexanes/EtOAc (5% to 50% EtOAc) provided S10 (477 mg, 1.53 mmol, 76% yield) as a yellow amorphous solid. ¹H NMR: (500 MHz, CDCl3) 8.10 (s, 1H), 7.60 – 7.54 (m, 1H), 7.20 (d, J = 7.1 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 5.9 Hz, 1H), 4.97 – 4.86 (m, 1H), 4.09 (dd, J = 6.1, 2.4 Hz, 2H), 2.93 – 2.86 (m, 1H), 2.82 – 2.69 (m, 2H), 2.27 (t, J = 2.4 Hz, 1H), 2.16 – 2.10 (m, 1H) ppm. ¹³C NMR: (126 MHz, CDCl3) 170.9, 169.3, 168.2, 167.5, 145.6, 136.2, 132.4, 117.2, 112.8, 111.4, 79.2, 72.2, 49.0, 32.3, 31.4, 22.8 ppm.

Synthesis of 2-(1-methyl-2,6-dioxopiperidin-3-yl)-4-(prop-2-yn-1-yloxy)isoindoline-1,3- dione) (S12). In a 2-dram capped vial equipped with a stir bar, S11 (150 mg, 480 mol, 1 eq.), DMF (2.4 mL), and K2CO3 (166 mg, 1.20 mmol, 2.5 eq.) were added and stirred for 10 minutes at room temperature. MeI (37 L, 600 mol, 1.25 eq.) was then added and the reaction stirred for 15 hours at room temperature. The solvent was removed under reduced pressure and the crude material was taken up in EtOAc (40 mL), washed with water (2 x 10 mL), brine (10 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using hexanes/EtOAc (0% to 20% EtOAc) gave 2 as a beige oil. TLC: Rf = 0.41 (20% EtOAc in hexanes, UV). ¹H NMR: (500 MHz, CDCl3) 7.70 (dd, J = 8.4, 7.3 Hz, 1H), 7.49 (dd, J = 7.3, 0.6 Hz, 1H), 7.38 (dd, J = 8.5, 0.5 Hz, 1H), 4.99 – 4.93 (m, 1H), 4.93 (d, J = 2.4 Hz, 2H), 3.18 (s, 3H), 2.99 – 2.90 (m, 1H), 2.81 – 2.73 (m, 2H), 2.58 (t, J = 2.4 Hz, 1H), 2.13 – 2.05 (m, 1H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.2, 168.7, 167.0, 165.7, 154.8, 136.3, 134.0, 119.8, 117.9, 116.8, 77.1, 56.9, 49.9, 31.9, 27.2, 22.0 ppm. HRMS: Calc’d for C17H15N2O5 [M+H⁺] 327.0975; found: 327.0980 Attorney Docket No.10110-450WO1

Synthesis of 2-(2,6-dioxopiperidin-3-yl)-4-((piperidin-4-ylmethyl)amino)isoindoline- 1,3-dione trifluoroacetic acid salt (S14). 2-(2,6-dioxopiperidin-3-yl)-4-((piperidin-4-ylmethyl)amino)isoindoline-1,3-dione trifluoroacetic acid salt (S12) was prepared according to previous reports.^9-10 Step1: In a 40 mL septum-capped reaction vial equipped with a stir bar, S8 (655 mg, 3.06 mmol, 1 eq.) was dissolved in DMSO (15 mL), then S13 (929 mg, 3.36 mmol, 1.1 eq.) and DIPEA (2.66 mL, 15.3 mmol, 5 eq.) were added. The reaction mixture was heated to 130 ºC for 3 hours, cooled to room temperature, and water (90 mL) was added. The resulting solid was collected by vacuum filtration and dried under vacuum to give int-S14 (1.22 g, 2.59 mmol, 85% yield) as a yellow solid that was used in the next step without further purification or characterization. TLC: Rf = 0.57 (20% EtOAc in DCM, UV). Step 2: In a 20 mL reaction vial equipped with a stir bar, int-S14 (447 mg, 950 mol, 1 eq.) was dissolved in DCM (5 mL) then TFA (2.37 mL, 31.4 mmol, 33 q.) was added and the reaction stirred for 5 hours at room temperature until full consumption of int-S14 was observed by LC–MS. The solvents were removed under reduced pressure to give S14 (418 mg, 863 mmol, 91% yield) as a yellow solid that was sufficiently pure by LC–MS and NMR to be used in the next

NMR: (500 MHz, DMSO) 11.10 (s, 1H), 8.62 (d, J = 11.4 Hz, 1H), 8.28 (d, J = 11.2 Hz, 1H), 7.58 (dd, J = 8.5, 7.0 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 7.0 Hz, 1H), 6.73 (s, 1H), 5.05 (dd, J = 12.8, 5.4 Hz, 1H), 3.32 – 3.24 (m, 4H), 2.94 – 2.78 (m, 3H), 2.63 – 2.46 (m, 2H), 2.07 – 2.00 (m, 1H), 1.94 – 1.80 (m, 3H), 1.42 – 1.30 (m, 2H) ppm. ¹³C NMR: (126 MHz, DMSO) 173.3, 170.6, 169.4, 167.7, 158.8 (q, J = 36.2 Hz), 146.9, 136.7, 132.7, 117.9, 116.2 (q, J = 292.0 Hz), 111.0, 109.6, 49.0, 46.9, 43.4, 33.4, 31.5, 26.6, 22.6 ppm. Attorney Docket No.10110-450WO1

Synthesis of 3-(((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)azetidin-1-ium trifluoroacetic acid salt (S16). Step 1: In a 20 mL septum capped vial equipped with a stir bar, S8 (102 mg, 0.548 mmol, 1 eq.) was added followed by DMA (5.5 mL, 0.1 M), S15 (151 mg, 0.548 mmol, 1 eq.), and DIPEA (0.286 mL, 1.64 mmol, 3 eq.) then capped and heated to 80 ºC for 24 hours. The reaction mixture was cooled to room temperature, water (10 mL) was added then extracted with EtOAc (3 x 20 mL). Combined organic layers were washed with water (10 mL), brine (15 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using DCM/MeOH (0 to 3%) provided the int-S16 (104 mg, 0.235 mmol, 43% yield) as a yellow oil. TLC: Rf = 0.51 (5% MeOH in DCM, UV). ¹H NMR: ^{(500 MHz, CDCl3}) 7.89 (s, 1H), 7.46 (dd, J = 8.5, 7.2 Hz, 1H), 7.07 (d, J = 7.1 Hz, 1H), 6.84 (d, J = 8.4 Hz, 1H), 6.20 (t, J = 5.8 Hz, 1H), 4.89 – 4.80 (m, 1H), 4.01 (t, J = 8.4 Hz, 2H), 3.61 (dd, J = 8.8, 5.0 Hz, 2H), 3.44 (dd, J = 7.5, 5.6 Hz, 2H), 2.86 – 2.80 (m, 1H), 2.79 – 2.65 (m, 3H), 2.13 – 2.03 (m, 1H), 1.37 (s, 9H) ppm. ¹³C NMR: (126 MHz, CDCl3) 170.8, 169.4, 168.1, 167.4, 156.3, 146.6, 136.3, 132.5, 116.5, 112.1, 110.6, 79.7, 48.9, 46.1, 31.4, 28.4, 28.2, 22.78 ppm. HRMS: Calc’d for C22H27N4O6 [M+H⁺] 443.1925; found: 443.1922. Step 2: In a 1-dram capped vial equipped with a stir bar, int-S16 (32 mg, 0.073 mmol, 1 eq.) was added followed by DCM (0.73 mL) and TFA (0.553 mL, 7.23 mmol, 100 eq.) then stirred at room temperature for 1.5 hours. The solvent and excess TFA were removed under vacuum to give S16 (31 mg, 0.068 mmol, 94% yield) as a yellow solid that was immediately used in the next step without further purification. Attorney Docket No.10110-450WO1 Synthesis of tert-butyl 4-(((2-(1-methyl-2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4- yl)amino)methyl)piperidine-1-carboxylate (S17). In a 20 mL capped vial equipped with a stir bar, S8 (250 mg, 0.905 mmol, 1 eq.) was added followed by DMF (5.5 mL) and K2CO3 (375 mg, 2.72 mmol, 3 eq.). The mixture was stirred at room temperature for 10 minutes then MeI (86 L, 1.36 mmol, 1.5 eq.) was added and the reaction stirred at room temperature for 1.5 hours until full consumption of S8 was observed by LC–MS, at which point S13 (194 mg, 0.905 mmol, 1 eq.) and DIPEA (946 L, 5.43 mmol, 6 eq.). The reaction mixture was heated to 90 ºC for 2 hours, cooled to room temperature and quenched with a solution of saturated aqueous NH4Cl (20 mL) then extracted with EtOAc (3 x 25 mL). Combined organic layers were washed with water saturated aqueous NH4Cl (15 mL), water (15 mL), and brine (15 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using hexanes/EtOAc (0 to 20% EtOAc) provided S17 (332 mg, 0.685 mmol, 76% yield) as a yellow solid. TLC: Rf = 0.48 (20% EtOAc in hexanes, UV). ¹H NMR: (500 MHz, CDCl3) 7.54 – 7.46 (m, 1H), 7.10 (d, J = 7.0 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.34 (t, J = 6.0 Hz, 1H), 4.95 – 4.86 (m, 1H), 4.21 – 4.08 (m, 1H), 3.22 (s, 3H), 3.18 (t, J = 6.1 Hz, 2H), 2.98 (dd, J = 12.9, 2.7 Hz, 1H), 2.83 – 2.64 (m, 4H), 2.13 – 2.07 (m, 1H), 1.82 – 1.75 (m, 2H), 1.60 – 1.52 (m, 4H), 1.46 (s, 9H) ppm.¹³C NMR: (126 MHz, CDCl3) 171.2, 169.8, 169.0, 167.7, 154.8, 147.0, 136.1, 132.6, 116.5, 111.6, 110.2, 79.6, 49.7, 48.3, 36.4, 31.9, 30.0, 28.5, 27.3, 22.2 ppm. HRMS: Calc’d for C25H32N4O6 [M+H⁺] 484.2322; found: 484.2326.

Synthesis of N-(1-methyl-2,6-dioxopiperidin-3-yl)-2-((piperidin-4- ylmethyl)amino)benzamide (S18). In a 2-dram reaction vial equipped with a stir bar, S17 (140 mg, 289 mmol, 1 eq.) was added followed by DCM (2.9 mL) then TFA (0.720 mL, 9.53 mmol, 33 eq.). The reaction stirred at room temperature for 3 hours. The solvent and TFA was removed under reduced pressure to give the TFA salt form that was freebased upon use by stirring in DCM and saturated aqueous Na2CO3 for 10 minutes then washed with brine (10 mL), dried over Na2SO4, Attorney Docket No.10110-450WO1 filtered and concentrated to give the desired free amine that was used in the next step without further purification. ¹H NMR: (500 MHz, DMSO) 7.58 (td, J = 7.7, 6.8, 5.1 Hz, 1H), 7.15 (d, J = 8.5 Hz, 1H), 7.03 (d, J = 7.0 Hz, 1H), 6.68 (t, J = 6.3 Hz, 1H), 5.12 (dd, J = 13.1, 5.3 Hz, 1H), 3.25 – 3.21 (m, 2H), 3.18 – 3.10 (m, 2H), 3.02 (s, 3H), 2.99 – 2.87 (m, 2H), 2.79 – 2.63 (m, 3H), 2.04 (dtd, J = 13.1, 5.4, 2.6 Hz, 1H), 1.80 – 1.74 (m, 2H), 1.32 – 1.23 (m, 4H) ppm. ¹³C NMR: (126 MHz, DMSO) 172.3, 170.3, 169.4, 167.7, 147.0, 136.8, 132.7, 117.9, 111.0, 109.5, 49.6, 47.4, 44.4, 34.6, 31.6, 28.3, 27.1, 21.9 ppm. HRMS: Calc’d for C20H24N4O6 [M+H⁺] 384.1798; found: 384.1793. Synthesis of TAF1 PROTACs Ceralasertib-based PROTACs:

Synthesis of (R)-(1-(2-(1-(8-azidooctyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-((R)-3- _{methylmorpholino)pyrimidin-4-yl)cyclopropyl)(imino)(methyl)- 6-sulfanone (S19).} In a 2-dram vial equipped with a stir bar, Ceralasertib (AZD6738) (75.0 mg, 0.181 mmol, 1 eq.), was dissolved in DMA (1.8 mL) then KOt-Bu (23.5 mg, 0.209 mmol, 1.15 eq.) was added and stirred at 0 ºC for 15 minutes followed by the addition of S2 (64.0 mg, 0.273 mmol, 1.5 eq.). The reaction mixture warmed to room temperature where it stirred for 12 hours. EtOAc (10 mL) was added, the reaction mixture filtered through a pad of celite, and the filtrate concentrated. The crude material was further purified by silica gel column chromatography using DCM/MeOH (0 to 3% MeOH gradient) to provide the desired products S19 (87 mg, 0.154 mmol, 85% yield) as a light-yellow oil. TLC: Rf = 0.36 (5% MeOH in DMC, UV). ¹H NMR: (600 MHz, CDCl3) 8.43 (d, J = 5.1 Hz, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.33 (d, J = 3.4 Hz, 1H), 7.27 (d, J = 3.5 Hz, 1H), 6.90 (s, 1H), 4.54 (s, 1H), 4.34 (t, J = 7.2 Hz, 2H), 4.15 (s, 1H), 4.07 (dd, J = 11.4, 3.7 Hz, 1H), 3.85 (d, J = 11.4 Hz, 1H), 3.77 (dd, J = 11.5, 3.0 Hz, 1H), 3.62 (td, J = 12.0, 3.0 Hz, 1H), 3.38 (td, J = 12.9, 3.9 Hz, 1H), 3.23 (t, J = 7.0 Hz, 2H), 3.16 (s, 3H), 1.92 – 1.86 (m, 2H), 1.82 – 1.78 (m, 2H), 1.59 – 1.54 (m, 4H), 1.39 (d, J = 6.8 Hz, 3H), 1.36 – 1.27 (m, 9H) ppm. ¹³CNMR: (126 Attorney Docket No.10110-450WO1 MHz, CDCl3) 163.8, 162.7, 162.3, 149.1, 142.4, 137.7, 129.2, 118.9, 115.3, 102.7, 101.1, 71.0, 66.8, 51.4, 48.6, 47.3, 44.8, 41.3, 39.4, 30.4, 29.1, 29.0, 28.8, 26.8, 26.6, 13.73, 12.7, 12.6 ppm. HRMS: Calc’d for C28H40N9O2S [M+H⁺] 566.3020; found: 566.3030.

Synthesis of ZS1-958. The title compound was prepared using O-propargyl thalidomide analog S11 purchased from Matrix Scientific. In a 2-dram septum-capped reaction vial equipped with a stir bar and argon balloon, S19 (17.0 mg, 30.1 mol, 1 eq.), S11 (9.40 mg, 30.1 mol, 1 eq.), CuSO4 (1.0 mg, 6.0 mol, 0.2 eq.), and sodium ascorbate (1.2 mg, 6.0 mol, 0.2 eq.) were added followed by THF (0.4 mL) and H2O (2 drops). The reaction stirred at room temperature for 15 hours until full consumption of S19 was achieved (determined by TLC and LCMS). Once complete, the reaction was diluted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated. Purification by preparative TLC using DCM/MeOH (5% MeOH) provided ZS1-958 (20.6 mg, 23.5 mol, 78% yield) as a light-yellow solid. TLC: Rf = 0.36 (5% MeOH in DMC,

5.0 Hz, 1H), 8.01 (d, J = 5.0 Hz, 1H), 7.71 (s, 1H), 7.67 (dd, J = 8.5, 7.3 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.31 (d, J = 3.4 Hz, 1H), 7.26 – 7.25 (m, 1H), 6.88 (s, 1H), 5.46 (s, 2H), 4.94 (dd, J = 12.1, 5.4 Hz, 1H), 4.59 – 4.48 (m, 1H), 4.35 – 4.29 (m, 4H), 4.16 (d, J = 13.0 Hz, 1H), 4.07 (dd, J = 11.5, 3.7 Hz, 1H), 3.85 (d, J = 11.5 Hz, 1H), 3.76 (dd, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.59 (m, 1H), 3.41 – 3.36 (m, 1H), 3.18 (s, 3H), 2.90 – 2.71 (m, 3H), 2.14 – 2.09 (m, 1H), 1.89 – 1.84 (m, 4H), 1.82 – 1.79 (m, 2H), 1.57 – 1.54 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.31 – 1.25 (m, 9H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.0, 168.2, 166.9, 165.8, 163.8, 162.7, 162.3, 155.7, 149.1, 143.1, 142.5, 137.6, 136.7, 133.7, 129.2, 123.0, 120.0, 118.9, 117.6, 116.5, 115.3, 102.7, 101.1, 71.0, 66.8, 63.5, 50.5, 49.2, 48.6, 47.2, 44.7, 41.2, 39.4, 31.5, 30.3, Attorney Docket No.10110-450WO1 30.1, 28.9, 28.8, 26.7, 26.3, 22.6, 13.7, 12.7, 12.5 ppm. HRMS: Calc’d for C44H52N11O7S [M+H⁺] 878.3766; found: 878.3761.

Synthesis of ZS1-959. In a 2-dram septum-capped reaction vial equipped with a stir bar and argon balloon, S19 (26.2 mg, 46.3 mol, 1 eq.), S11 (15.1 mg, 46.3 mol, 1 eq.), CuSO4 (1.5 mg, 9.3 mol, 0.2 eq.), and sodium ascorbate (1.8 mg, 9.3 mol, 0.2 eq.) were added followed by THF (0.46 mL) and H2O (23 L). The reaction stirred at room temperature for 12 hours then diluted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography using DCM/MeOH (0 to 5% MeOH) provided ZS1-959 (28.1 mg, 31.5 mol, 68% yield) as a beige solid. TLC: Rf = 0.41 (5% MeOH in DMC, UV). ¹H NMR: (500 MHz, CDCl3) 8.42 (d, J = 5.1 Hz, 1H), 8.02 (d, J = 5.0 Hz, 1H), 7.71 (s, 1H), 7.67 (dd, J = 8.5, 7.3 Hz, 1H), 7.50 – 7.45 (m, 2H), 7.32 (d, J = 3.5 Hz, 1H), 7.27 (s, 1H), 6.90 (s, 1H), 5.47 (s, 2H), 4.99 – 4.90 (m, 1H), 4.53 (s, 1H), 4.36 – 4.29 (m, 4H), 4.16 (d, J = 13.0 Hz, 1H), 4.07 (dd, J = 11.5, 3.8 Hz, 1H), 3.88 – 3.82 (m, 1H), 3.76 (dd, J = 11.5, 3.2 Hz, 1H), 3.61 (dd, J = 11.7, 3.0 Hz, 1H), 3.38 (td, J = 12.8, 4.0 Hz, 1H), 3.20 (s, 3H), 3.18 (s, 3H), 3.00 – 2.93 (m, 1H), 2.84 – 2.69 (m, 2H), 2.12 – 2.06 (m, 1H), 1.91 – 1.84 (m, 4H), 1.83 – 1.77 (m, 2H), 1.57 (dt, J = 5.3, 3.1 Hz, 2H), 1.38 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 14.1 Hz, 9H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.1, 168.8, 167.1, 165.9, 163.7, 162.6, 162.3, 155.7, 143.1, 136.6, 133.8, 129.2, 123.0, 120.0, 117.7, 116.5, 115.3, 102.8, 101.2, 71.0, 70.6, 66.8, 63.5, 60.4, 50.5, 49.9, 48.6, 47.3, 44.8, 41.3, 39.4, 31.9, 30.4, 30.1, 30.0, 29.7, 28.9, 28.8, 27.3, 26.7, 26.3, 22.0, 13.7, 12.7, 12.9 ppm. HRMS: Calc’d for C45H54N11O7S [M+H⁺] 892.3923; found: 892.3919. Attorney Docket No.10110-450WO1

Synthesis of ZS1-998. In a 2-dram septum-capped reaction vial equipped with a stir bar and argon balloon, S19 (35.0 mg, 62.0 mol, 1 eq.), 21 (19.3 mg, 61.9 mol, 1 eq.), sodium ascorbate (2.5 mg, 12 mol, 0.2 eq.), and CuSO4 (2 mg, 12 mol, 0.2 eq.) were added followed by THF (0.46 mL) and H2O (23 L). The reaction stirred at room temperature for 8 hours then diluted with EtOAc (10 mL), dried over Na2SO4, filtered and concentrated. Purification by preparative TLC using DCM/MeOH (5% MeOH) provided ZS1-998 (41.1 mg, 46.9 mol, 76% yield) as a yellow solid. TLC: Rf = 0.32 (5% MeOH in DMC, UV). ¹H NMR: (500 MHz, CDCl3) 8.52 (s, 1H), 8.42 (d, J = 5.2 Hz, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.50 – 7.42 (m, 2H), 7.35 – 7.28 (m, 2H), 7.12 (d, J = 7.1 Hz, 1H), 6.98 (d, J = 8.5 Hz, 1H), 6.91 (s, 1H), 6.67 (t, J = 5.9 Hz, 1H), 4.90 (ddd, J = 12.2, 5.1, 1.5 Hz, 1H), 4.63 (d, J = 6.0 Hz, 2H), 4.58 – 4.47 (m, 1H), 4.37 (t, J = 7.0 Hz, 2H), 4.29 (t, J = 7.3 Hz, 2H), 4.20 – 4.12 (m, 1H), 4.08 (dd, J = 11.5, 3.5 Hz, 1H), 3.86 (d, J = 11.5 Hz, 1H), 3.76 (dd, J = 11.5, 3.0 Hz, 1H), 3.65 – 3.58 (m, 1H), 3.38 (td, J = 12.8, 3.9 Hz, 1H), 3.19 (s, 3H), 2.91 – 2.67 (m, 3H), 2.14 – 2.08 (m, 1H), 1.90 – 1.79 (m, 6H), 1.58 – 1.53 (m, 2H), 1.38 (d, J = 6.8 Hz, 3H), 1.33 – 1.27 (m, 9H) ppm. ¹³C NMR: (126 MHz, CDCl3) 171.0, 169.4, 168.4, 167.5, 163.4, 162.6, 162.3, 146.2, 145.1, 136.2, 132.4, 129.6, 127.8, 121.4, 119.5, 117.1, 115.3, 113.9, 112.3, 110.8, 103.1, 101.6, 71.0, 66.7, 50.4, 49.0, 48.5, 47.3, 45.1, 41.1, 39.4, 38.8, 31.5, 30.3, 30.1, 29.7, 28.9, 28.7, 26.6, 26.3, 22.8, 13.8, 12.7, 12.5 ppm. HRMS: Calc’d for C44H53N12O6S [M+H⁺] 877.3926; found: 877.3928. Attorney Docket No.10110-450WO1

The starting material (S20) was prepared according to our previous report.¹ In a 20 mL septum capped vial equipped with a stir bar and argon balloon, S20 (132 mg, 0.256 mmol, 1 eq.) and DMF (2.5 mL) were added followed by K2CO3 (70.6 mg, 0.511 mmol, 2.0 eq.) then stirred at room temperature for 10 minutes. S2 (71.8 mg, 0.307 mmol, 1.2 eq.) was added and the reaction mixture stirred at room temperature for 13 hours. EtOAc (20 mL) was added and filtered through a pad of Celite while rinsing with EtOAc. The filtrate was concentrated to give a crude oil that was purified by silica gel column chromatography using DCM/MeOH (0% to 5% MeOH) to give 52 (125 mg, 0.187 mmol, 73% yield) as a beige oil. TLC: R^f = 0.41 (5% MeOH in DMC, UV). ¹H NMR: (500 MHz, CDCl3) 8.15 (d, J = 1.4 Hz, 1H), 8.09 (s, 1H), 8.07 (d, J = 1.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 3.5 Hz, 1H), 7.55 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 6.53 (d, J = 3.5 Hz, 1H), 5.78 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.07 – 4.94 (m, 2H), 4.27 (t, J = 7.2 Hz, 2H), 4.09 (t, J = 7.5 Hz, 2H), 3.99 (s, 3H), 3.25 (t, J = 6.9 Hz, 2H), 2.49 (q, J = 7.0 Hz, 2H), 2.41 (s, 3H), 1.97 – 1.92 (m, 2H), 1.59 – 1.55 (m, 2H), 1.41 – 1.22 (m, 8H) ppm. HRMS: Calc’d for C35H40N7O5S [M+H⁺] 670.2806; found: 670.2800. Attorney Docket No.10110-450WO1

In a 2-dram capped reaction vial equipped with a stir bar was 52 (118 mg, 0.176 mmol, 1 eq.) in MeOH (1.8 mL) at 70 C. 1 M NaOH (0.758 mL, 0.758 mmol, 4.3 eq.) was added dropwise to the heated solution while stirring then continued heating for an additional 3 hours. The reaction mixture was cooled to room temperature and the solvent removed under reduced pressure. H²O (8 mL) was added and washed with EtOAc (3 x 8 mL). The pH of the aqueous layer was adjusted to a pH of 3 with 1 M HCl and back extracted with EtOAc (3 x 15 mL). The combined organic layers from the back extraction were dried over Na2SO4, filtered and concentrated to give 53 (73 mg, 0.146 mmol, 83% yield) as light-beige oil that solidified to an amorphous solid upon standing. The crude material was sufficiently pure by LCMS and was used in the next step without further purification. TLC: Rf = 0.21 (10% MeOH in DMC, UV). ¹H NMR: (500 MHz, DMSO) 12.84 (br. s, 1H), 12.11 (s, 1H), 8.48 (s, 1H), 8.17 (d, J = 1.5 Hz, 1H), 8.14 (d, J = 1.5 Hz, 1H), 7.94 (s, 1H), 7.37 (t, J = 2.7 Hz, 1H), 6.42 (t, J = 2.3 Hz, 1H), 5.89 (ddt, J = 17.0, 10.2, 6.7 Hz, 1H), 5.11 (dd, J = 17.2, 1.8 Hz, 1H), 5.03 (dd, J = 10.3, 1.9 Hz, 1H), 4.37 (t, J = 7.1 Hz, 2H), 4.15 (t, J = 7.3 Hz, 2H), 3.29 (t, J = 6.9 Hz, 3H), 1.88 – 1.80 (m, 2H), 1.54 – 1.47 (m, 2H), 1.34 – 1.24 (m, 8H) ppm. HRMS: Calc’d for C27H32N7O3 [M+H⁺] 502.2561; found: 502.2559.

In a 2-dram capped reaction vial equipped with a stir bar was 53 (66 mg, 0.132 mmol, 1 eq.) in DMF (1.3 mL) at room temperature. 54 (22.7 L, 0.263 mmol, 2 eq.), HATU (100 mg, 0.263 mmol, 2 eq.) and Et3N (36.7 L, 0.263 mmol, 2 eq.) were added then heated to 40 C for 72 hours. The reaction mixture was cooled to room temperature and the solvent was Attorney Docket No.10110-450WO1 removed under reduced pressure. The crude reaction mixture was directly adsorbed to silica gel and purified by silica gel column chromatography using DCM/MeOH (0% to 5% MeOH) to provide 55 (67 mg, 0.117 mmol, 89% yield) as a beige oil. TLC: Rf = 0.36 (5% MeOH in DMC, UV). ¹H NMR: (500 MHz, CDCl3) 11.13 (s, 1H), 8.09 (s, 1H), 7.60 (s, 1H), 7.54 (d, J = 8.6 Hz, 2H), 7.30 – 7.27 (m, 1H), 6.42 (s, 1H), 5.85 (ddt, J = 17.0, 10.3, 6.8 Hz, 1H), 5.07 (dd, J = 28.6, 13.7 Hz, 2H), 4.27 – 4.18 (m, 4H), 3.80 – 3.66 (m, 6H), 3.25 (t, J = 6.9 Hz, 2H), 2.64 – 2.55 (m, 2H), 1.98 – 1.88 (m, 2H), 1.57 (q, J = 7.1 Hz, 2H), 1.42 – 1.28 (m, 10H) ppm. ¹³C NMR: (126 MHz, CDCl3) 170.6, 154.5, 144.1, 140.0, 134.4, 134.2, 130.6, 130.2, 129.4, 128.7, 127.4, 124.0, 120.1, 117.5, 112.8, 108.7, 103.3, 66.9, 51.4, 48.7, 46.0, 45.7, 34.1, 31.0, 29.8, 29.0, 28.8, 26.8, 26.6, 8.6 ppm. HRMS: Calc’d for C31H39N8O3 [M+H⁺] 571.3140; found: 571.3144.

In a 1-dram septum capped reaction vial equipped with a stir bar and argon balloon, S21 (25.0 mg, 44 mol, 1 eq.), S11 (14.0 mg, 44 mol, 1 eq.), sodium ascorbate (1.7 mg, 8.8 mol, 0.2 eq.), and CuSO4 (1.4 mg, 8.8 mol, 0.2 eq.) were added followed by THF (0.9 mL) and H2O (20 L). The reaction mixture was sonicated under argon for three minutes then stirred at room temperature until completion. After 1.5 hours at room temperature, 0.2 equivalents of sodium ascorbate, CuSO4 and S11 were added to achieve full consumption of S21. Once complete, the reaction was diluted with EtOAc (15 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel preparative TLC (8% MeOH in DCM) provided ZS3-024 (22.4 mg, 25.4 mol, 58% yield) as a beige foam. TLC: Rf = 0.38 (8% MeOH in DCM, UV) ¹H NMR: (500 MHz, DMSO) 12.09 (s, 1H), 11.10 (s, 1H), 8.41 (s, 1H), 8.26 (s, 1H), 7.88 – 7.80 (m, 2H), 7.73 (d, J = 8.6 Hz, 1H), 7.68 (s, 1H), 7.48 (d, J = 7.2 Hz, 2H), 7.35 (app.t, J = 2.8 Hz, 1H), 6.38 (app. t, J = 2.3 Hz, 1H), 5.94 – 5.82 (m, 1H), 5.41 (s, 2H), 5.16 – 4.99 (m, 3H), 4.36 (t, J = 7.1 Hz, 2H), 4.31 (t, J = 7.0 Hz, 2H), 4.14 (t, J = 7.2 Hz, 2H), 3.71 – 3.47 (m, 8H), 2.93 – 2.82 (m, 1H), 2.62 – 2.43 (m, 3H), 2.05 – 1.97 (m, 2H), 1.85 – 1.75 (m, 4H), 1.34 – 1.15 (m, 8H) ppm. ¹³C NMR: (126 MHz, DMSO) Attorney Docket No.10110-450WO1 173.2, 170.4, 170.0, 167.2, 165.7, 155.7, 154.0, 145.7, 142.3, 137.4, 135.6, 134.5, 133.8, 130.3, 130.1, 129.3, 128.6, 127.4, 125.2, 123.9, 120.8, 117.6, 117.0, 116.1, 111.3, 108.8, 103.3, 66.6, 62.7, 49.8, 49.2, 47.3, 44.8, 34.2, 31.4, 30.1, 29.9, 28.8, 28.7, 26.5, 26.2, 22.4, 14.4 ppm. HRMS: Calc’d for C47H51N10O8 [M+H⁺] 883.3886; found: 883.3883.

In a 1-dram septum capped reaction vial equipped with a stir bar and argon balloon, S21 (20 mg, 35 mol, 1 eq.), S10 (11 mg, 35 mol, 1 eq.), sodium ascorbate (1.4 mg, 7.0 mol, 0.2 eq.), and CuSO4 (1.1 mg, 7.0 mol, 0.2 eq.) were added followed by THF (0.8 mL) and H2O (20 L). The reaction mixture was sonicated under argon for three minutes then stirred at room temperature until completion. After 1.5 hours at room temperature, 0.2 equivalents of sodium ascorbate, CuSO4 and S10 were added to achieve full consumption of S21. Once complete, the reaction was diluted with EtOAc (15 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography using DCM/MeOH (0% to 8% MeOH) provided ZS3-025 (22.2 mg, 25.2 mol, 72% yield) as a yellow solid. TLC: Rf = 0.34 (8% MeOH in DCM, UV) ¹H NMR: (500 MHz, DMSO) 12.08 (s, 1H), 11.09 (s, 1H), 8.37 (s, 1H), 7.99 (s, 1H), 7.85 (s, 1H), 7.66 (d, J = 1.2 Hz, 1H), 7.55 (dd, J = 8.5, 7.2 Hz, 1H), 7.45 (d, J = 1.3 Hz, 1H), 7.34 (app. t, J = 2.8 Hz, 1H), 7.14 (d, J = 8.6 Hz, 1H), 7.07 – 7.02 (m, 2H), 6.37 (app. t, J = 2.4 Hz, 1H), 5.93 – 5.82 (m, 1H), 5.12 – 5.00 (m, 3H), 4.57 (d, J = 6.0 Hz, 2H), 4.29 (app. q, J = 6.6 Hz, 4H), 4.13 (t, J = 7.2 Hz, 2H), 3.76 – 3.47 (m, 8H), 2.93 – 2.81 (m, 1H), 2.61 – 2.51 (m, 3H), 2.05 – 1.96 (m, 2H), 1.82 – 1.71 (m, 4H), 1.25 – 1.23 (m, 6H), 1.18 – 1.14 (m, 2H) ppm.¹³C NMR: (126 MHz, DMSO) 173.3, 170.5, 170.1, 169.2, 167.7, 154.0, 150.2, 146.3, 144.9, 142.3, 136.6, 135.6, 132.6, 130.2, 129.3, 127.4, 123.9, 123.2, 120.1, 118.1, 117.6, 111.4, 111.4, 110.2, 108.8, 103.3, 66.6, 49.7, 49.0, 47.3, 44.7, 38.2, 34.2, 31.4, 30.1, 29.9, 28.8, 28.7, 26.5, 26.2, 22.6, 14.7 ppm. HRMS: Calc’d for C47H52N11O7 [M+H⁺] 882.4046; found: 882.4042. Attorney Docket No.10110-450WO1

In a 2-dram reaction vial equipped with a stir bar, S20 (214 mg, 0.413 mmol, 1 eq.) and DMF (2.1 mL) were added followed by K2CO3 (115 mg, 0.829 mmol, 2 eq.) then stirred at room temperature for 10 minutes. Electrophilic linker S5 (126 mg, 0.497 mmol, 1.2 eq.) was added and the reaction stirred at room temperature for 48 hours. Once complete (determined by TLC and LCMS), the reaction was diluted with EtOAc (15 mL), quenched with saturated aqueous NaHCO3 (10 mL), and extracted with EtOAc (3 x 15 mL). Combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using DCM/acetone (0% to 20% acetone gradient) provided S25 (246 mg, 0.366 mmol, 88% yield) as a light-yellow oil after containing 5-10% of an undesired regioisomer. Purification of the major isomer was performed by reverse phase column chromatography using water (0.1% formic acid)/MeCN (0.1% formic acid) (0 to 50% MeCN gradient). TLC: Rf = 0.31 (60% EtOAc in hexanes, UV) ¹H NMR: (500 MHz, CDCl3) 8.13 (d, J = 1.4 Hz, 1H), 8.04 (d, J = 1.4 Hz, 1H), 8.02 – 7.98 (m, 3H), 7.90 (d, J = 3.5 Hz, 1H), 7.54 (s, 1H), 7.28 (d, J = 8.4 Hz, 2H), 6.53 (d, J = Attorney Docket No.10110-450WO1 3.5 Hz, 1H), 5.77 (ddt, J = 17.1, 10.2, 6.8 Hz, 1H), 5.07 – 4.94 (m, 2H), 4.81 (t, J = 4.7 Hz, 1H), 4.24 (t, J = 7.2 Hz, 2H), 4.07 (t, J = 7.3 Hz, 2H), 3.98 (s, 3H), 3.96 – 3.92 (m, 2H), 3.85 – 3.80 (m, 2H), 2.49 (q, J = 7.2 Hz, 2H), 2.40 (s, 3H), 1.98 – 1.89 (m, 2H), 1.67 – 1.60 (m, 2H), 1.46 – 1.34 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 167.3, 152.5, 145.2, 145.0, 144.7, 136.3, 136.1, 134.4, 134.2, 133.0, 130.8, 129.4, 128.6, 127.7, 125.0, 123.2, 123.1, 117.4, 111.2, 110.9, 106.3, 104.4, 64.9, 52.4, 48.8, 45.5, 33.8, 33.6, 29.8, 28.9, 26.7, 23.8, 21.7 ppm. HRMS: Calc’d for C36H41N4O7S [M+H⁺] 673.2690; found: 673.2684.

Step 1: In a 2-dram vial equipped with a stir bar, compounds of general structure 3 (1 eq.) were dissolved in MeOH (0.1 M) followed by the addition of NaOH (1 M, 4.3 eq.). The resulting reaction mixture was heated to 70 ºC for 6-15 hours until full consumption of 3 then cooled to room temperature. The solvent was removed under reduced pressure and the crude material was taken up in DCM. Water and NaOH (1 M) was added to adjust the pH (>10). The aqueous layer was extracted with DCM (2 x) and discarded. The remaining aqueous layer was acidified to pH 3-2 with HCl (2 M), let stand for 5 minutes. The resulting solid was collected by filtration while rinsing with water then dried under vacuum to give int-S26 (112 mg, 0.222 mmol, 74% yield) as an off-white amorphous solid that was used in the next step without further purification.¹H NMR: (500 MHz, MeOD) 8.36 (s, 1H), 8.26 (d, J = 1.4 Hz, 1H), 8.22 (d, J = 1.4 Hz, 1H), 7.66 (s, 1H), 7.38 (d, J = 2.9 Hz, 1H), 6.46 (d, J = 2.7 Hz, 1H), 5.91 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.11 (dd, J = 17.2, 1.6 Hz, 1H), 5.07 – 5.02 (m, 1H), 4.77 (t, J = 4.7 Hz, 1H), 4.40 (t, J = 7.1 Hz, 2H), 4.27 – 4.21 (m, 2H), 3.92 – 3.87 (m, 2H), 3.82 – 3.76 (m, 2H), 2.62 (q, J = 7.2 Hz, 2H), 2.00 – 1.93 (m, 2H), 1.60 – 1.56 (m, 2H), 1.44 – 1.35 (m, 6H) ppm. Exchangeable protons were not detected. ¹³C NMR: (126 MHz, MeOD) 168.7, 154.6, 146.1, 143.8, 134.5, 134.1, 130.7, 129.1, 128.4, 128.0, 127.4, 125.6, 123.4, 116.5, 113.0, 111.3, 104.2, 102.8, 64.4, 44.9, 33.8, 33.3, 29.4, 28.6, 26.2, 23.4, 19.9 ppm. HRMS: Calc’d for C28H33N4O5 [M+H⁺] 505.2445 found: 505.2440. Attorney Docket No.10110-450WO1 Step 2: In a 2-dram capped reaction vial equipped with a stir bar, int-S26 (110 mg, 0.218 mmol, 1 eq.) was added and DMF (2.2 mL) followed by morpholine (37.6 L, 0.436 mmol, 2 eq.), Et3N (60.8 L, 0.436 mmol, 2 eq.), and HATU (166 mg, 0.436 mmol, 2 eq.). The resulting reaction mixture stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc (15 mL) and partitioned with sat. aq. NH4Cl (10 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL), combined organic layers were dried over Na2SO4, filtered and concentrated. Further purification by column chromatography using DCM/MeOH (0 to 6% MeOH gradient) provided S26 (119 mg, 0.207 mmol, 95% yield) as an off-white foam. TLC: Rf = 0.29 (5% MeOH in DCM, UV) ¹H NMR: (500 MHz, CDCl3) 10.71 (s, 1H), 7.98 (s, 1H), 7.67 (s, 1H), 7.54 (dd, J = 12.8, 1.2 Hz, 2H), 7.28 (t, J = 2.8 Hz, 1H), 6.48 (t, J = 2.4 Hz, 1H), 5.89 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.13 (dd, J = 17.1, 1.5 Hz, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.83 (t, J = 4.7 Hz, 1H), 4.23 (dt, J = 12.8, 7.2 Hz, 4H), 3.98 – 3.93 (m, 2H), 3.90 – 3.52 (m, 10H), 2.63 (q, J = 7.1 Hz, 2H), 1.99 – 1.90 (m, 2H), 1.68 – 1.62 (m, 2H), 1.47 – 1.36 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl3) 170.9, 154.6, 144.2, 142.6, 134.6, 134.5, 130.2, 129.8, 129.6, 129.2, 126.7, 124.3, 120.5, 117.4, 112.5, 108.3, 104.4, 103.6, 67.0, 64.9, 48.5, 45.4, 34.2, 33.7, 29.8, 29.0, 26.8, 23.8 ppm. HRMS: Calc’d for C32H40N5O5 [M+H⁺] 574.3024; found: 574.3020.

In a 20 mL septum capped vial equipped with a stir bar was added 4d (365 mg, 0.636 mmol, 1 eq.) followed by acetone/H2O (5.3 mL/1 mL, 0.1 M) and p-TSA (127 mg, 0.668 mmol, 1.05 eq.). The reaction mixture stirred at room temperature for 5 hours then the solvent was removed under reduced pressure. The crude mixture was taken up in EtOAc (100 mL) and washed with sat. aq. NaHCO3 (3 x 15 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel column chromatography using hexanes/Acetone (0 to 8% MeOH gradient) provided 13 (309 mg, 0.583 mmol, 92% yield) as a colorless oil which was used immediately in the next step. TLC: Rf = 0.39 (8% MeOH in DCM, UV) LC–MS: M+H⁺ = 530.2 Attorney Docket No.10110-450WO1

In a 20 mL septum capped vial equipped with a stir bar and argon balloon, S27 (203 mg, 0.383 mmol, 1 eq.) and S14 (223 mg, 0.460 mmol, 1.2 eq.) were added followed by MeOH (4 mL), AcOH (34.5 L, 0.575 mmol, 0.5 eq.), NaOAc (94 mg, 1.15 mmol, 3 eq.) and NaCNBH3 (72 mg, 1.15 mmol, 3 eq.). The reaction mixture stirred at room temperature for 4.5 hours then was quenched by the addition of water (15 mL). The aqueous layer was extracted with EtOAc (3 x 30 mL), combined organic layers were washed with brine (2 x 15 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel column chromatography using DCM/MeOH (0 to 10% MeOH) provided ZS3-046 (267 mg, 0.383 mmol, 79% yield) as a yellow solid. Additional purification by reverse phase chromatography [H2O (0.1% formic acid)/MeCN (0.1% formic acid), 0 to 50% MeCN gradient] was used to supply the material for in vivo assays with a purity of >99% by

0.39 (10% MeOH in DCM, UV) ¹H NMR: (500 MHz, CDCl3) 10.09 (s, 1H), 8.98 (s, 1H), 8.46 (s, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 7.55 – 7.45 (m, 3H), 7.11 (d, J = 7.0 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.45 (t, J = 2.2 Hz, 1H), 6.29 (t, J = 5.7 Hz, 1H), 5.88 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.17 – 5.09 (m, 1H), 5.06 (d, J = 10.2 Hz, 1H), 4.92 (dd, J = 12.3, 5.4 Hz, 1H), 4.23 (q, J = 6.6 Hz, 4H), 3.74 (s, 8H), 3.24 (d, J = 10.8 Hz, 2H), 3.21 – 3.14 (m, 2H), 2.92 – 2.84 (m, 1H), 2.80 – 2.70 (m, 2H), 2.62 (q, J = 7.1 Hz, 2H), 2.59 – 2.53 (m, 2H), 2.28 – 2.17 (m, 2H), 2.16 – 2.09 (m, 1H), 1.92 (q, J = 6.6 Hz, 2H), 1.85 (d, J = 12.7 Hz, 2H), 1.73 – 1.50 (m, 5H), 1.36 – 1.27 (m, 6H) ppm. ¹³C NMR: (126 MHz, CDCl³) 171.3, 170.8, 169.6, 168.8, 167.7, 167.5, 154.5, 146.8, 144.3, 142.7, 136.2, 134.5, 134.4, 132.5, 130.3, 129.9, 129.5, 129.2, 126.5, 124.3, 120.5, 117.5, 116.6, 112.7, 111.8, 110.2, 108.4, 103.8, 67.0, 57.6, 52.4, 49.0, 48.5, 47.8, 45.4, 35.3, 34.2, 31.5, 29.5, 28.6, 28.4, 26.9, 26.4, 24.8, 22.9 ppm. HRMS: Calc’d for C49H57N9O7 [M+H⁺] 884.4454; found 884.4449. Purity: Determined to be >99% pure by HPLC (UV, 250 nm and 210 nm). Attorney Docket No.10110-450WO1

In a 1-dram septum capped vial equipped with a stir bar and argon balloon, S27 (11 mg, 21 mol, 1 eq.) and S16 (11.4 mg, 25 mol, 1.2 eq.) were added followed by MeOH (0.5 mL), AcOH (0.6 L, 10.4 mol, 0.5 eq.), NaOAc (5.1 mg, 62.3 mol, 3 eq.) and NaCNBH3 (3.9 mg, 62.3 mol, 3 eq.). The reaction mixture stirred at room temperature for 3 hours then was quenched by the addition of water (5 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL), combined organic layers were washed with brine (2 x 5 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel preparative TLC (10% MeOH in DCM) provided ZS3-047 (10 mg, 11.7 mol, 56% yield) as a yellow amorphous solid. TLC: Rf = 0.37 (10% MeOH in DCM, UV) ¹H NMR: (500 MHz, MeOD) 8.31 (s, 1H), 7.71 (d, J = 1.4 Hz, 1H), 7.63 (s, 1H), 7.57 – 7.52 (m, 2H), 7.35 (d, J = 2.8 Hz, 1H), 7.06 (t, J = 8.0 Hz, 2H), 6.42 (d, J = 2.8 Hz, 1H), 5.89 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.11 (dd, J = 17.2, 1.7 Hz, 1H), 5.07 – 5.01 (m, 2H), 4.39 (t, J = 6.9 Hz, 2H), 4.23 (t, J = 7.4 Hz, 2H), 3.90 – 3.54 (m, 13H), 3.51 (d, J = 6.8 Hz, 2H), 3.30 – 3.24 (m, 2H), 2.96 – 2.86 (m, 1H), 2.86 – 2.80 (m, 1H), 2.74 (dt, J = 6.0, 3.1 Hz, 1H), 2.62 (dq, J = 14.3, 7.4 Hz, 4H), 2.24 – 2.14 (m, 1H), 2.12 – 2.04 (m, 1H), 1.94 (p, J = 6.9 Hz, 2H), 1.35 (dt, J = 5.4, 2.8 Hz, 6H) ppm. HRMS: Calc’d for C47H53N9O7 [M+H⁺] 856.4141; found 856.4139.

Attorney Docket No.10110-450WO1 In a 1-dram septum capped vial equipped with a stir bar and argon balloon, S27 (9 mg, 17 mol, 1 eq.) and S16 (10 mg, 20.4 mol, 1.2 eq.) were added followed by MeOH (0.5 mL), AcOH (0.5 L, 8.5 mol, 0.5 eq.), NaOAc (4.2 mg, 51 mol, 3 eq.) and NaCNBH3 (3.2 mg, 51 mol, 3 eq.). The reaction mixture stirred at room temperature for 7 hours then was quenched by the addition of water (5 mL). The aqueous layer was extracted with EtOAc (3 x 10 mL), combined organic layers were washed with brine (2 x 5 mL), dried over Na2SO4, filtered and concentrated. Further purification by silica gel preparative TLC (10% MeOH in DCM) provided ZS3-061 (9.3 mg, 10.5 mol, 62% yield) as a yellow oil. TLC: Rf = 0.40 (10% MeOH in DCM, UV) ¹H NMR: (500 MHz, CDCl3) 9.78 (s, 1H), 7.99 (s, 1H), 7.67 (s, 1H), 7.53 (d, J = 5.9 Hz, 2H), 7.50 – 7.47 (m, 1H), 7.30 – 7.27 (m, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.88 (dd, J = 8.5, 3.8 Hz, 1H), 6.49 (t, J = 2.3 Hz, 1H), 6.31 (t, J = 6.0 Hz, 1H), 5.88 (ddt, J = 17.0, 10.2, 6.8 Hz, 1H), 5.12 (dd, J = 17.1, 1.4 Hz, 1H), 5.09 – 5.04 (m, 1H), 4.93 – 4.89 (m, 1H), 4.22 (q, J = 7.0 Hz, 4H), 3.91 – 3.55 (m, 10H), 3.26 – 3.18 (m, 7H), 2.98 (dd, J = 12.8, 2.5 Hz, 1H), 2.79 – 2.74 (m, 2H), 2.61 (q, J = 7.1 Hz, 2H), 2.22 (t, J = 7.6 Hz, 1H), 2.11 – 2.06 (m, 1H), 2.04 – 1.98 (m, 1H), 1.91 (d, J = 6.7 Hz, 4H), 1.70 – 1.62 (m, 5H), 1.39 – 1.26 (m, 6H) ppm. HRMS: Calc’d for C50H59N9O7 [M+H⁺] 898.0780; found 898.0786. References for Additional Experimental Details for Example 2 1. Karim, R. M.; Yang, L.; Chen, L.; Bikowitz, M. J.; Lu, J.; Grassie, D.; Shultz, Z. P.; Lopchuk, J. M.; Chen, J.; Schonbrunn, E., Discovery of Dual TAF1-ATR Inhibitors and Ligand-Induced Structural Changes of the TAF1 Tandem Bromodomain. J. Med. Chem. 2022, 65 (5), 4182-4200. 2. Shultz, Z. P.; Scattolin, T.; Wojtas, L.; Lopchuk, J. M., Stereospecific - (hetero)arylation of sulfoximines and sulfonimidamides. Nat. Synth.2022, 1 (2), 170-179. 3. Botta, M.; Maccari, G.; Sanfilippo, S.; De Luca, F.; Docquier, J.-D.; Deodato, D. Preparation of linear guanidine derivatives as antibacterial agents. WO2016055644, 2016. 4. Berton, G.; Pizzini, S.; Fabris, F.; Bertolin, T.; Pafumi, E.; Ceccon, L.; Daelemans, J.; Borsato, G.; Scarso, A.; Piazza, R.; Ferretti, P., Synthesis of C37-Alkenones for Past Climate Reconstructions. Eur. J. Org. Chem.2020, 2020 (24), 3542-3551. 5. Zang, Y.; Qu, Y.; Aoki, T.; Teraguchi, M.; Kaneko, T.; Jia, H.; Ma, L.; Miao, F., Simultaneous improvement of permeability and selectivity in enantioselective permeation through solid chiral membranes from a newly synthesized one-handed helical Attorney Docket No.10110-450WO1 polyphenylacetylene with aldehyde pendant groups by enantioselective reaction. Polymer 2019, 171, 45-49. 6. Qi, J.; Armstrong, S.; Wu, L. Compounds, compositions, and methods for targeted protein degradation of SMARCA2 and SMARCA4. WO2020264172, 2020. 7. Phillips, A. J.; Nasveschuk, C. G.; Henderson, J. A.; Liang, Y.; Fitzgerald, M. E.; Michael, R. E. Preparation of bromodomain targeting degronimers for target protein degradation. WO2017197056, 2017. 8. Yang, K.; Song, Y.; Xie, H.; Wu, H.; Wu, Y.-T.; Leisten, E. D.; Tang, W., Development of the first small molecule histone deacetylase 6 (HDAC6) degraders. Bioorg. Med. Chem. Lett.2018, 28 (14), 2493-2497. 9. Mainolfi, N.; Ji, N.; Kluge, A. F.; Weiss, M. M.; Zhang, Y.; Zheng, X. Preparation of bifunctional compounds as IRAK degraders and uses thereof. WO2020113233, 2020. 10. Liu, J.; Plewe, M. B.; Wang, J.; Han, X.; Chen, L. Preparation of pyrazolopyridines and related heterocycles as CBP and p300 degradation bivalent compds for treatment of diseases. WO2020173440, 2020 The compositions and methods of the appended claims are not limited in scope by the specific compositions and methods described herein, which are intended as illustrations of a few aspects of the claims and any compositions and methods that are functionally equivalent are intended to fall within the scope of the claims. Various modifications of the compositions and methods in addition to those shown and described herein are intended to fall within the scope of the appended claims. Further, while only certain representative compositions and method steps disclosed herein are specifically described, other combinations of the compositions and method steps also are intended to fall within the scope of the appended claims, even if not specifically recited. Thus, a combination of steps, elements, components, or constituents may be explicitly mentioned herein; however, other combinations of steps, elements, components, and constituents are included, even though not explicitly stated.

Claims

Attorney Docket No.10110-450WO1 WHAT IS CLAIMED IS: 1. A compound of Formula I A-L-B (I) or a pharmaceutically acceptable salt or derivative thereof; wherein: A is selected from

a double bond; B is an E3 ubiquitin ligase-recruiting moiety;

X¹ is selected from -N(R^x)-, -O-, -S-, and 3- to 8-membered monocyclic or bicyclic heterocycle optionally substituted with one or more groups selected from Z; Y¹ is selected from O and NH; X² is absent or -N(R^x)-; Z is independently selected at each occurrence from hydrogen, halo, nitro, cyano, azido, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 alkenyl, C2-C6 alkynyl, (C3-C6 cycloalkyl)(C0-C3 alkyl)-, (3- to 8-membered monocyclic or bicyclic heterocycle)-(C0-C3 alkyl)-, (6- to 10-membered monocyclic or bicyclic aryl)-(C0-C3 alkyl)-, (5- to 10- membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, R^xO-(C0-C3 alkyl)-, R^xS-(C0- C3 alkyl)-, (R^xR^yN)-(C0-C3 alkyl)-, R^xO-C(O)-(C0-C3 alkyl)-, R^xS-C(O)-(C0-C3 alkyl)-, (R^xR^yN) C(O)-(C0-C3 alkyl)-, R^xO-S(O)2-(C0-C3 alkyl)-, (R^xR^yN) S(O)2-(C0-C3 alkyl)-, R^zC(O)-O-(C0-C3 alkyl)-, R^zC(O)-(R^xN)-(C0-C3 alkyl)-, R^zS(O)2-O-(C0-C3 alkyl)-, R^zS(O)2- (R^xN)-(C0-C3 alkyl)-, R^zC(O)-(C0-C6 alkyl)-, R^zS(O)-(C0-C3 alkyl)-, and R^zS(O)2-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more groups selected from Y as allowed by valency; R^x and R^y are independently selected at each occurrence from hydrogen, C1-C6alkyl, C1-C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, each of which may be optionally substituted with one or more Y groups as allowed by valency; R^z is independently selected at each occurrence from hydrogen, halo, C1-C6alkyl, C1- C6haloalkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7cycloalkyl)-(C0-C3 alkyl)-, (4- to 6- membered heterocycle)-(C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic aryl)- (C0-C3 alkyl)-, (5- to 10-membered monocyclic or bicyclic heteroaryl)-(C0-C3 alkyl)-, -OR^x, -SR^x, and -NR^xR^y, each of which may be optionally substituted with one or more Y groups as allowed by valency; and Attorney Docket No.10110-450WO1 Y is independently selected at each occurrence from alkyl, haloalkyl, alkoxy, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl, heterocycle, aldehyde, amino, carboxylic acid, ester, ether, halo, hydroxy, keto, nitro, cyano, azido, oxo, silyl, sulfo-oxo, sulfonyl, sulfone, sulfoxide, sulfonylamino, or thiol. 2. The compound of claim 1, wherein L is -L¹-Q¹-L²-.

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. 4. The compound of claim 2 or claim 3, wherein L¹ is C1-C6 alkyl. 5. The compound of claim 2 or claim 3, wherein L¹ is . 6. The compound of any one of claims 2-5, wherein L² is C1-C6 alkyl. 7. The compound of any one of claims 2-5, wherein L² is . 8. The compound of claim 1, wherein L is -L¹-Q²-L²-Q³-.

wherein X³ and X⁴ are independently selected from CH and N; and n1 and n2 are independently 1 or 2. Attorney Docket No.10110-450WO1 10. The compound of claim 8, wherein Q² is

. The compound of any one of claims 8-10, wherein Q³ is selected from

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. 12. The compound of any one of claims 8-11, wherein L¹ is C1-C6 alkyl. 13. The compound of any one of claims 8-11, wherein L¹ is

. 14. The compound of any one of claims 8-13, wherein L² is C1-C6 alkyl. 15. The compound of any one of claims 8-13, wherein L² is

. 16. The compound of claim 1, wherein L is -L¹-Q⁴-L²-. 17. The compound of claim 16, wherein X¹ is selected from -NH-, -O-, -S-,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. 18. The compound of claim 16 or claim 17, wherein Y¹ is O. 19. The compound of claim 16 or claim 17, wherein Y¹ is NH. 20. The compound of any one of claims 16-19, wherein X² is absent. 21. The compound of any one of claims 16-19, wherein X² is NH. 22. The compound of any one of claims 16-21, wherein L¹ is C1-C6 alkyl. Attorney Docket No.10110-450WO1 23. The compound of any one of claims 16-21, wherein L¹ is

. 24. The compound of any one of claims 16-23, wherein L² is C1-C6 alkyl. 25. The compound of any one of claims 16-23, wherein L² is . 26. The compound of claim 1, wherein L is -Q⁵-L¹-Q⁶-. 27. The compound of claim 26, wherein Q⁵ is selected from

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. . The compound of claim 26 or claim 27, wherein Q⁶ is selected from

,

wherein X³ is selected from CH and N; and n1 and n2 are independently 1 or 2. 29. The compound of any one of claims 26-28, wherein L¹ is C1-C6 alkyl. 30. The compound of any one of claims 26-28, wherein L¹ is

. 31. The compound of any one of claims 1-30, wherein B is selected from:

Attorney Docket No.10110-450WO1

wherein: X⁵ is a bond or selected from -NH-, -O-, and -CH2-; R¹ is hydrogen or -CH2-O-C(=O)-O-(C1-C6 alkyl); X⁶ is selected from CH and N; R² is selected from hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy; and X⁷ is selected from O and NH. 32. A pharmaceutical composition comprising a compound of any one of claims 1-31, or a pharmaceutically acceptable salt or derivative thereof, and a pharmaceutically acceptable carrier or excipient. 33. A method of treating cancer in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-31, or a pharmaceutically acceptable salt or derivative thereof, or a pharmaceutical composition of claim 32. 34. The method of claim 35, wherein the cancer is a TAF1-associated cancer.