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WO2025129032A1 - Inhibiteurs de chd1l pour le traitement du cancer - Google Patents

Inhibiteurs de chd1l pour le traitement du cancer Download PDF

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Publication number
WO2025129032A1
WO2025129032A1 PCT/US2024/060084 US2024060084W WO2025129032A1 WO 2025129032 A1 WO2025129032 A1 WO 2025129032A1 US 2024060084 W US2024060084 W US 2024060084W WO 2025129032 A1 WO2025129032 A1 WO 2025129032A1
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Prior art keywords
alkyl
compound
nhc
alkylene
halogen
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English (en)
Inventor
Daniel V. Labarbera
Qiong ZHOU
Paul AWOLADE
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University of Colorado System
University of Colorado Colorado Springs
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University of Colorado System
University of Colorado Colorado Springs
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Publication of WO2025129032A1 publication Critical patent/WO2025129032A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • CRC Colorectal Cancer
  • CRC Colorectal Cancer
  • FIG.1 shows a workflow for CHD1L inhibitor discovery.
  • CHD1Li are selected from either HTS hits or analogs developed. They are then subjected to different in vitro assays in the “testing funnel” to filter out the less promising hits or analogs.
  • FIGs.2A-2B show top hits exhibiting dose-dependent inhibition of CHD1L and tumor organoid viability.
  • SEM standard error of the mean
  • FIG.4A-4B show CHD1Li Inhibit CSC Stemness in CRC cells.
  • FIG.4B shows a representative images (25 stitched fields of view on 10x air objective) of 2D SW620-GFP+ colonies treated with CHD1Li for 10 days at 0.25-8 ⁇ M and stained with Hoechst dye for imaging. All images were obtained using the Opera Phenix.
  • FIGs.5A-5E show predicted fl-CHD1L allosteric binding site and binding poses of hit CHD1Li.
  • FIG.5A depicts fl-CHD1L structure showing the most plausible CHD1Li binding site.
  • the domain architecture is depicted in cartoon representation as N-ATPase, C-ATPase, macro domain and linker region.
  • FIG.5B-5E depict the 3D representation of the predicted binding pose for the CHD1Li as indicated.
  • the non-bonded interactions are depicted as hydrogen bond, pi-cation, and pi-pi stacking.
  • FIG.6A (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site.
  • FIG.6A illustrates CHD1L inhibitor Compound 9 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period.
  • FIG.6B (left) illustrates a graph showing the root mean square distance in nanometers (nm) as a function of time in nanoseconds (ns) for CHD1L_CA and CHD1L C-ATPase allosteric site.
  • FIG.6B (right) illustrates CHD1L inhibitor Compound 4 in the allosteric pocket or binding site as a 2-D representation of protein-ligand contacts over the 500 ns simulation period.
  • FIG.7 shows a schematic summary of mechanism of CHD1Li actions.
  • FIGs.8A-8B show predicted binding interaction of two example compounds of CHD1L inhibitors (CHD1Li), compound 25 and compound 42, respectively.
  • FIG.9A illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 30) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • FIG.9B illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 32) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • FIG.9C illustrates a graph of enzyme activity (%) of CHD1L versus the log(Compound 33) concentration (in ⁇ M), where the IC 50 was determined to be about 1.75 ⁇ M.
  • SEM standard error of the mean
  • FIGs.10A-10C show plots demonstrating CHD1L trapping of example compounds disclosed herein visualizing the correlation between CHD1L trapping and 20-hour treatment with the example compound at different concentrations in the SUM149PT cancer cell line.
  • the data has been derived from two independent experiments, with the mean value indicated, and a standard deviation of 3 samples.
  • FIG.10A illustrates a graph of CHD1L trapping as a function of Compound 30 concentration (after 20-hour treatment with Compound 30).
  • FIG.10B illustrates a graph of CHD1L trapping as a function of Compound 32 concentration (after 20- hour treatment with Compound 32).
  • FIG.10C illustrates a graph of CHD1L trapping as a function of Compound 33 concentration (after 20-hour treatment with Compound 33).
  • FIG. 11A illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 30 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • FIG.11B illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 32 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • FIG.11C illustrates a graph of tumor organoid viability (in %) as a function of the concentration of Compound 33 (in ⁇ M), where the tumor organoids tested were HCT116, SW620, MDA-MB- 231, SUM149PT, and Miapaca-2, and the corresponding IC50 values are shown.
  • DETAILED DESCRIPTION DEFINITIONS [0019] 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 invention belongs. All patents and publications referred to herein are incorporated by reference. [0020] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise.
  • an agent includes a plurality of such agents
  • the cell includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth.
  • ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulas, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included.
  • the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range.
  • C1-Cx includes C1-C2, C1-C3... C1-Cx.
  • a group designated as “C 1 -C 4 ” indicates that there are one to four carbon atoms in the moiety, i.e., groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms.
  • “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, and t-butyl.
  • Alkyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, or more preferably, from one to six carbon atoms, wherein an sp 3 -hybridized carbon of the alkyl residue is attached to the rest of the molecule by a single bond.
  • Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl- 1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3- methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl
  • C 1 -C 6 alkyl means that the alkyl group consists of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated.
  • the alkyl is a C 1 -C 10 alkyl, a C 1 -C 9 alkyl, a C 1 -C 8 alkyl, a C 1 -C 7 alkyl, a C 1 -C 6 alkyl, a C 1 -C 5 alkyl, a C 1 -C 4 alkyl, a C1-C3 alkyl, a C1-C2 alkyl, or a C1 alkyl.
  • an alkyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , - SR a , -OC(O)R a , -OC(O)-OR f , -N(R a )2, -N + (R a )3, -C(O)R a , -C(O)OR a , -C(O)N(R a )2, - N(R a )C(O)OR f , -OC(O)-N(R a )2, -N(R a )C(O)R a , -N(R a )S(O)tR f (where t is 1 or 2), -S(O)tOR a (where
  • Alkenyl refers to an optionally substituted straight-chain, or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms, wherein an sp 2 -hybridized carbon or an sp 3 -hybridized carbon of the alkenyl residue is attached to the rest of the molecule by a single bond.
  • the group may be in either the cis or trans conformation about the double bond(s), and should be understood to include both isomers.
  • an alkenyl group is optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.
  • an alkenyl group is optionally substituted as described below by one or more of the following substituents: halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl, -OR a , -SR a , -OC(O)-R f , -OC(O)-OR f , -N(R a ) 2 , -N + (R a ) 3 , - C(O)R a , -C(O)OR a , -C(O)N(R a )2, -N(R a )C(O)OR f , -OC(O)-N(R a )2, -N(R a )C(O)R f , - N(R a )S(O)tR f (where t is 1 or 2), -S(O)t
  • Alkynyl refers to an optionally substituted straight-chain or optionally substituted branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms, wherein an sp-hybridized carbon or an sp 3 -hybridized carbon of the alkynyl residue is attached to the rest of the molecule by a single bond. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like.
  • optionally substituted alkyl means either “alkyl” or “substituted alkyl” as defined above.
  • an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono- substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH 2 CHF 2 , -CH 2 CF 3 , -CF 2 CH 3 , -CFHCHF 2 , etc.).
  • substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • substitution or substitution patterns e.g., substituted alkyl includes optionally substituted cycloalkyl groups, which in turn are defined as including optionally substituted alkyl groups, potentially ad infinitum
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • the compounds described herein exist as “geometric isomers.” In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti,
  • Z isomers as well as the corresponding mixtures thereof. In some situations, compounds exist as tautomers.
  • a “tautomer” refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds presented herein exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist.
  • tautomeric equilibrium includes: [0054]
  • the compounds described herein possess one or more chiral centers and each center exists in the (R)- configuration or (S)- configuration.
  • the compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof.
  • mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein.
  • the compounds described herein are prepared as optically pure enantiomers by chiral chromatographic resolution of the racemic mixture.
  • the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers.
  • dissociable complexes are preferred (e.g., crystalline diastereomeric salts).
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • the term “positional isomer” refers to structural isomers around a central ring, such as ortho-, meta-, and para- isomers around a benzene ring.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and eth
  • salt or “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art.
  • Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • determining means determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of” can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.
  • subject can be a biological entity containing expressed genetic materials.
  • the biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa.
  • the subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro.
  • the subject can be a mammal.
  • the mammal can be a human.
  • the subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.
  • the term “in vivo” is used to describe an event that takes place in a subject’s body.
  • the term “ex vivo” is used to describe an event that takes place outside of a subject’s body.
  • ex vivo assay is not performed on a subject. Rather, it is performed upon a sample separate from a subject.
  • An example of an ex vivo assay performed on a sample is an “in vitro” assay.
  • the term “in vitro” is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained.
  • In vitro assays can encompass cell-based assays in which living or dead cells are employed.
  • In vitro assays can also encompass a cell-free assay in which no intact cells are employed.
  • treatment or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient.
  • Beneficial or desired results include but are not limited to a therapeutic benefit and/or a prophylactic benefit.
  • a therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated.
  • a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder.
  • a prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.
  • a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.
  • “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not.
  • “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.
  • the section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.
  • Chromodomain Helicase DNA Binding Protein 1 Like (also known as amplified in liver cancer 1, ALC1) is an oncogene that promotes tumor progression, metastasis, and multidrug resistance (MDR) in many cancers such as lung cancer, breast cancer, and colorectal cancer (CRC).
  • CHD1L is an oncogene and its amplification and overexpression in patients is a marker of metastatic cancer, poor prognosis, low survival, and multidrug resistance (MDR).
  • CHD1L functions at the interface of malignant gene expression and tumor cell survival.
  • CRC is the third most prevalent cancer diagnosed each year and CRC patients have the second highest mortality rate worldwide.
  • CHD1L is an oncogene overexpressed in many cancer types. Elevated CHD1L expression may be a biomarker for poor prognosis, poor survival, and metastasis in various cancers, including CRC.
  • CHD1L is influenced by key cancer-driving pathways, including Wnt/ ⁇ -catenin, PI3K/AKT, and Ras/MAPK. Its diverse roles encompass regulating malignant gene expression, cell plasticity and stemness via epithelial-mesenchymal transition (EMT), cell survival, and metastatic potential. Given the critical role of CHD1L in tumor progression, metastasis, and drug resistance, the identification of CHD1L inhibitors (CHD1Li) could lead to effective targeted therapies for CRC and other cancers. [0073] Presented herein are CHD1L inhibitors (CHD1Li) that display potent antitumor activity through allosteric inhibition of CHD1L ATPase, which induces programmed cell death.
  • CHD1Li CHD1L inhibitors
  • the present disclosure provides a compound having a structure of Formula (I): Formula (I), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C1-C6 alkyl), -NH2, -NH(C1-C6 alkyl), -NH(C1-C6 alkyl)2, -(C1-C6 alkylene)-OH, and -(C 1 -C 6 alkylene)-NH 2 , 3- to 9-membered carbocycle, or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-
  • the 3- to 9-membered carbocycle and 3- to 9-membered heterocycle are optionally substituted with one or more R b ;
  • R 1 is -H. In some embodiments, R 1 is -(C1-C6 alkyl). In some embodiments, R 1 is -(C 2 -C 6 alkenyl). In some embodiments, R 1 is -(C 2 -C 6 alkynyl). In some embodiments, R 1 is halogen. In some embodiments, R 1 is -(C 1 -C 6 haloalkyl). In some embodiments, R 1 is -OH. In some embodiments, R 1 is -O(C1-C6 alkyl). In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -NH(C1-C6 alkyl).
  • R b is C 3 -C 9 heterocycle.
  • L 1 is -NH-*.
  • L 1 is . 1 some embodiments, L is .
  • R 3 is .
  • Y is S.
  • Y is N.
  • W is N.
  • W is C.
  • R 1 is pyrrolyl. In some embodiments, R 1 is tetrahydropyrrolyl. In some embodiments, R 1 is thiophenyl.
  • the compound having a structure of Formula (I) is selected from , and .
  • the compound has a structure of Formula (III-A): , or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein Ring A is selected from phenyl, pyridinyl, pyrimidinyl, furanyl, and thiophenyl, and wherein Ring A is optionally substituted with one or more R b .
  • R 1 is -C(CH 3 ) 3 . In some embodiments, R 1 is -phenyl. In some embodiments, R 1 is pyridinyl. In some embodiments, R 1 is pyrimidinyl. In some embodiments, R 1 is furanyl. In some embodiments, R 1 is thiophenyl. In some embodiments, R 1 is pyrazolyl. In some embodiments, R 1 is pyrrolyl. In some embodiments, R 1 is tetrahydropyrrolyl. In some embodiments, R 1 is thiophenyl. In some embodiments, R 1 is optionally substituted with one or more R a .
  • the compound of Formula (III-B) is selected from: , , , , , , and , or a pharmaceutically acceptable salt, tautomer, or solvate thereof. [0103] In some embodiments, the compound is selected from:
  • the compound of Formula (V) is: 11: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 12: 3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one; 13: 5-ethyl-3-phenylpyrazolo[1,5-a]pyrimidin-7-ol; 14: 5-(tert-butyl)-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidine; 15: 5-ethyl-3-(4-fluorophenyl)pyrazolo[1,5-a]pyrimidin-7-ol; 16: 3-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol;
  • the present disclosure also provides a compound of Formula (IV): Formula (IV), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: Ring B is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle, wherein the 3- to 9-membered carbocycle or 3- to 9-membered heterocycle is optionally substituted with one or more R b ; R a and R b are each independently selected at each occurrence from -(C 1 -C 6 alkyl), -(C 2 -C 6 alkenyl), -(C 2 -C 6 alkynyl), -OH, -O(C 1 -C 6 alkyl), -(C 1 -C 6 alkylene)-OH, -NH 2 , -NH(C 1 -C 6 alkyl), -N(C1-C6 alkyl)2, -(C1-C6 alkylene)-NH2, -NH
  • Ring B is a 3- to 9-membered carbocycle. In some embodiments, Ring B is a 3- to 9-membered heterocycle. In some embodiments, Ring B is a 3- membered heterocycle. In some embodiments, Ring B is a 4-membered heterocycle. In some embodiments, Ring B is a 5-membered heterocycle. In some embodiments, Ring B is a 6- membered heterocycle. In some embodiments, the heterocycle has at least one heteroatom selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has two heteroatoms independently selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycle has a heteroatom selected from nitrogen, oxygen, and sulfur.
  • the heterocycle has at least one nitrogen atom. In some embodiments, the heterocycle has a nitrogen atom. In some embodiments, the heterocycle has two nitrogen atoms. In some embodiments, the heterocycle has at least one oxygen atom. In some embodiments, the heterocycle has a oxygen atom. In some embodiments, the heterocycle has one nitrogen atom and one oxygen atom. [0107] In some embodiments, when Ring B is , then R x is other than pyridinyl. [0108] In some embodiments, when Ring B is and R x is pyridinyl, then R x is substituted with one or more R n .
  • R x is -(C1-C6 alkyl). In some embodiments, R x is -(C2-C6 alkenyl). In some embodiments, R x is -(C2-C6 alkynyl). In some embodiments, R x is -OH. In some embodiments, R x is -O(C 1 -C 6 alkyl). In some embodiments, R x is -(C1-C6 alkylene)-OH. In some embodiments, R x is -NH2. In some embodiments, R x is - NH(C 1 -C 6 alkyl). In some embodiments, R x is -N(C 1 -C 6 alkyl) 2 .
  • R x is C3-C9 heterocycle.
  • when two or more R x are taken together with the C atom to which they are bound to form n is an integer from 1 to 5.
  • n is 1.
  • n is 2.
  • n is 3.
  • n is 4.
  • n is 5.
  • R n is - (C 1 -C 6 alkyl). In some embodiments, R n is -(C 2 -C 6 alkenyl). In some embodiments, R n is -(C 2 -C 6 alkynyl). In some embodiments, R n is -OH. In some embodiments, R n is -O(C1-C6 alkyl). In some embodiments, R n is -(C1-C6 alkylene)-OH. In some embodiments, R n is -NH2. In some embodiments, R n is -NH(C 1 -C 6 alkyl). In some embodiments, R n is -N(C 1 -C 6 alkyl) 2 .
  • the present disclosure provides a method of treating a proliferative disease comprising administering a compound having a structure of Formula (V) to a subject in need thereof, the compound having a structure of Formula (V): Formula (V), or a pharmaceutically acceptable salt, tautomer, or solvate thereof, wherein: R 1 is selected from -H, -(C1-C6 alkyl), -(C2-C6 alkenyl), -(C2-C6 alkynyl), halogen, -(C1-C6 haloalkyl), -OH, -O(C 1 -C 6 alkyl), -NH 2 , -NH(C 1 -C 6 alkyl), -NH(C 1 -C 6 alkyl) 2 , -(C 1 -C 6 alkylene)-OH, and -(C 1 -C 6 alkyl
  • R 1 is -H. In some embodiments, R 1 is -(C1-C6 alkyl). In some embodiments, R 1 is -(C2-C6 alkenyl). In some embodiments, R 1 is -(C2-C6 alkynyl). In some embodiments, R 1 is halogen. In some embodiments, R 1 is -(C 1 -C 6 haloalkyl). In some embodiments, R 1 is -OH. In some embodiments, R 1 is -O(C1-C6 alkyl). In some embodiments, R 1 is -NH2. In some embodiments, R 1 is -NH(C1-C6 alkyl).
  • R 1 is -NH(C1- C 6 alkyl) 2 . In some embodiments, R 1 is -(C 1 -C 6 alkylene)-OH. In some embodiments, R 1 is -(C 1 - C 6 alkylene)-NH 2 . [0117] In some embodiments, R 1 is a 3- to 9-membered carbocycle or 3- to 9-membered heterocycle. In some embodiments, R 1 is phenyl, pyridinyl, pyrimidyl, furanyl, thiophenyl, naphthyl, or indolyl. In some embodiments, R 1 is phenyl. In some embodiments, R 1 is pyridinyl.
  • Ring A is pyridinyl. In some embodiments, Ring A is pyrimidinyl. In some embodiments, Ring A is furanyl. In some embodiments, Ring A is thiophenyl. In some embodiments, Ring A is substituted with at least one R b .
  • the administering the compound of any one of Formulas (V)- (IX) reduces an average tumor cell size by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, at most 90%, or at most 100%. In some embodiments, administering the compound of any one of Formulas (V)-(IX) reduces an average tumor cell size by 20% to 80%, 40% to 90%, 60% to 100%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between.
  • the proliferative disease comprises a T cell factor (TCF)-driven cancer.
  • the method comprises inhibiting chromatin helicase DNA- binding protein 1-like (CHD1L).
  • the inhibiting of CHD1L comprises determining a loss of ATPase activity.
  • the determining comprises performing an ATPase activity assay.
  • the method comprises trapping CHD1L onto chromatin.
  • the trapping comprises increasing an amount of CHD1L by 1-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold.
  • the trapping comprises increasing an amount of CHD1L by at most 1-fold, at most 2-fold, at most 3-fold, at most 4-fold, at most 5-fold, at most 6-fold, at most 7-fold, at most 8-fold, at most 9-fold, or at most 10-fold.
  • the TCF-driven cancer comprises colorectal cancer or metastatic colorectal cancer.
  • the present disclosure provides a method of reducing catalytic activity of a CHD1L.
  • the method comprises contacting the CHD1L with a compound of any one of Formulas (I)-(IX).
  • the catalytic activity of the CHD1L is an ATPase activity.
  • the catalytic activity of the CHD1L is reduced by about 10% to about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, or about 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.
  • the catalytic activity of the CHD1L is reduced by at most 10%, at most 20%, at most 30%, at most 40%, at most 50%, at most 60%, at most 70%, at most 80%, or at most 90%. In some embodiments, the catalytic activity of the CHD1L is reduced by 20% to 70%, 40% to 90%, 60% to 80%, 30% to 80%, or 50% to 90%, including all values and sub ranges in between. [0155] In some embodiments, the catalytic activity is measured by an ATPase assay. [0156] In some embodiments, the compound is selected from: ,
  • the method comprises binding a CHD1L inhibitor to an allosteric binding site of CHD1L.
  • binding a CHD1L inhibitor comprises binding the CHD1L inhibitor to a CHD1L having at least about 70% sequence identity to SEQ ID NO: 1.
  • binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a lysine in the allosteric binding site. In some instances, the lysine is lysine-273 (K273).
  • binding a CHD1L inhibitor comprises exposing the CHD1L inhibitor to a tyrosine in the allosteric binding site.
  • the glutamate is tyrosine 480 (Y480).
  • the CHD1L comprises any one of SEQ ID NOs: 1-39.
  • the CHD1L comprises a sequence selected from Table 3. Table 3. CHD1L Sequences.
  • Cell Culture –cells were grown within RPMI 1640 media (Gibco, Ref#: 11875-093) containing 5% fetal bovine serum (Gibco, Ref#: 10437028) in 10 cm tissue culture coated dishes (Fisher Scientific, Ref#: FB012924). Cells were stored in a 37°C humidified incubator at 5% CO 2 for growth. Cells were split by aspirating media from the plate, washing with 5 mL of Phosphate Buffer Solution (PBS) 1X pH 7.4 (Gibco, Ref#: 10010-023), followed by addition of 0.25% Trypsin (Life Technologies, Ref#: 25200072) in media, prior to incubation for 6 minutes.
  • PBS Phosphate Buffer Solution
  • EMT Dual Reporter Assay The EMT dual reporter assay was performed. SW620- GFP+ cells were plated as 3D organoids and treated with 0-40 ⁇ M of CHD1Li as described above.
  • the 100 ⁇ L reaction solution consisted of 0.5 mg/mL microsomes, phosphate buffer pH 7.4 (44 mM KH2PO4, 56 mM K2HPO4), 1.94 mg/mL UDPGA (Sigma Aldrich, Ref# U6751), 25 ⁇ g alamethicin (Sigma-Aldrich, A4665), 1 mM MgCl2, 1 mM NADPH (Sigma-Aldrich, Ref# 481973-50MG), 1% DMSO, and 10 ⁇ M of either CHD1Li or testosterone (Sigma, T1500-1G) for control tubes.
  • the mass spectrometer was operated in the ESI+ mode and all settings were optimized by manually tuning to infused standard solutions.
  • Global mass spectrometer parameter settings were selected to give the highest average sensitivity for all compounds of interest.
  • Global mass spectrometer settings are as follows: curtain gas, 40 psi; collision gas, high; ion spray voltage, 4500 V; source temperature, 700°C; ion source gas 1 and 2, 50 psi; entrance potential, 10 V; and collision cell exit potential, 14 V.
  • the collision energy (CE) and declustering potential (DP) were optimized separately for each compound.
  • Data was collected using the multiple reaction monitoring (MRM) mode. Quantitation was performed using an external calibration curve for each compound.
  • Analytical separation was achieved with a Phenomenex kinetex C18 column [2.1 x 100 mm, 2.6 ⁇ m]. The column was held at 40°C and eluted at 0.6 mL/min with a gradient of 0.1% formic acid (A) and 0.1% formic acid in 9:1 acetonitrile:water (B) with a total runtime of 10 minutes. Chromatographic separation was achieved with a linear gradient (time, % of solvent B): 0-0.5 min, 5% B; 0.5-4.5 min, 5-55% B; 4.5-6.5 min, 55-94% B; 6-7 min, 94-5% B; and then isocratic for 3 minutes at 5% B to re-equilibrate the column.
  • the 3D low energy conformation of hit compounds 8- 11 was created with the LigPrep module. Ligands ionization and tautomeric states were generated using Epik at pH 7.0 ⁇ 2.0.
  • the 3D model of fl-CHD1L (UniProt# Q86WJ1) in the active state was downloaded from AlphaFold database and processed using the protein preparation workflow. A reliability check of the minimized protein structure was conducted prior to its use for further calculations. [0171] Binding Site Elucidation.
  • the minimized fl-CHD1L structure was characterized for potential druggable sites using the SiteMap module. The minimum site points per site were set at 15 while using a more restrictive requirement for hydrophobicity to exclude sites occupying free space.
  • the returned sites were ranked based on the site score, drugability score, size, and volume.
  • ⁇ Gbind Molecular Docking and Binding Free Energy ( ⁇ Gbind) Estimation.
  • the minimized structures of hit CHD1Li 8-11 and fl-CHD1L were used as inputs for molecular docking calculations using the induced-fit docking (IFD) protocol at the best site identified from SiteMap calculations.
  • the receptor grid box was defined as the centroid of amino acid residues bordering the selected binding site with an inner and outer box size of 10 and 30 ⁇ , respectively.
  • the ligand ring conformations were sampled at 2.5 kcalmol-1, followed by a short minimization of the protein structure to RMSD 0.18 ⁇ and Prime refinement of residues within 5 ⁇ of binding site.
  • Ligands were then redocked into receptor structures within 30 kcalmol-1 using extra- precision Glide docking.
  • the ⁇ Gbind for the resulting CHD1L complexes were estimated using Prime molecular mechanics/generalized Born surface area (MM/GBSA) module.
  • MM/GBSA generalized Born surface area
  • VSGB variable- dielectric generalized Born model
  • All atoms of binding site residues were minimized during the calculation to account for ligand-induced conformational changes.
  • the best pose for each hit compound was determined using the docking score, glide model, glide energy, IFD score and ⁇ Gbind.
  • MD Molecular Dynamics
  • a non-linear regression model was used to create a logarithmic curve to model the inhibitor vs response variable slope and calculate the half maximal inhibitory concentration (IC50) of each compound within a 95% confidence interval. Normalization to control and EC2-fold calculations were performed in Microsoft Excel for MacOS (version 16.76) [0176] Results [0177] Hits were reexamined for their potential as CHD1Li using a tailored hit-to-lead validation schema to prioritize additional hits as leads for further optimization (FIG.1). Compound 6 was used as reference and positive control and is described at PCT Pub. No. WO 2021/195279 A1, the entirety of which is incorporated by this reference.
  • the compounds were first tested against the cat-CHD1L recombinant enzyme ATPase assay to confirm inhibitory activity and eliminate false positives from the HTS. Once confirmed as hits, they are tested for their ability to induce cytotoxicity or inhibit or reverse EMT, using CRC tumor organoids models. [0178] Select hits were next examined for their ability to inhibit CSC stemness, using the clonogenic colony formation assay.
  • the mesenchymal phenotype of SW620 cells was selected for the cell-based assays in this validation scheme since it displays enhanced tumorigenic properties, including multidrug resistance and CSC stemness. Therefore, this phenotype has the highest potential for colony formation, metastasis, and represents an aggressive CRC tumor cell model .
  • CHD1L Enzyme Inhibition – confirmed hits from primary HTS were re-evaluated for their dose dependent inhibition of cat-CHD1L ATPase.
  • Compounds 32-36 were deprioritized due to their limited potency with inhibition concentration 50% (IC50) values >20 ⁇ M. All the other compounds displayed relatively potent CHD1L inhibition with IC50 ⁇ 15 (Table 4).
  • Hit compounds 8-11 displayed similar inhibitory activity compared to Compound 6 and were prioritized for further validation (Table 4 and FIG.2A).

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Abstract

L'invention concerne des composés et des méthodes pour le traitement du cancer.
PCT/US2024/060084 2023-12-15 2024-12-13 Inhibiteurs de chd1l pour le traitement du cancer Pending WO2025129032A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195279A2 (fr) * 2020-03-24 2021-09-30 The Regents Of The University Of Colorado, A Body Corporate Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal
US20230103444A1 (en) * 2020-03-24 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectal cancer
WO2023055763A2 (fr) * 2021-09-30 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021195279A2 (fr) * 2020-03-24 2021-09-30 The Regents Of The University Of Colorado, A Body Corporate Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal
US20230103444A1 (en) * 2020-03-24 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Small molecule inhibitors of oncogenic chd1l with preclinical activity against colorectal cancer
WO2023055763A2 (fr) * 2021-09-30 2023-04-06 The Regents Of The University Of Colorado, A Body Corporate Inhibiteurs à petites molécules de chd1l oncogènes présentant une activité préclinique contre le cancer colorectal

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