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WO2025076115A1 - Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques - Google Patents

Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques Download PDF

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Publication number
WO2025076115A1
WO2025076115A1 PCT/US2024/049630 US2024049630W WO2025076115A1 WO 2025076115 A1 WO2025076115 A1 WO 2025076115A1 US 2024049630 W US2024049630 W US 2024049630W WO 2025076115 A1 WO2025076115 A1 WO 2025076115A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
subject
administration
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2024/049630
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English (en)
Inventor
Krishna Vaddi
Peggy SCHERLE
Neha BHAGWAT
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Prelude Therapeutics Inc
Original Assignee
Prelude Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Prelude Therapeutics Inc filed Critical Prelude Therapeutics Inc
Publication of WO2025076115A1 publication Critical patent/WO2025076115A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Compound l is a potent and selective inhibitor of CDK9 with a biochemical half-maximal inhibitory concentration (IC50) of 0.98 nM at 1 mM adenosine triphosphate that inhibits the enzymatic activity of human CDK9/CyclinTl complex.
  • IC50 biochemical half-maximal inhibitory concentration
  • FIG. 1 shows an exemplary study design.
  • DL5 (15 mg/m 2 ) was evaluated as an intermediate DL following safety review of DL4 (18 mg/m 2 ).
  • Compound I was administered IV QW in a 3-week cycle until disease progression or unacceptable toxicity.
  • FIG. 2 is a chart showing the dosing scheme.
  • the safety evaluable set includes all patients who received at least 1 dose of Compound I.
  • FIG. 3 is a chart showing duration of the study follow-up including patent status. Status indicates the primary reason for treatment discontinuation.
  • the text on the bars after baseline (SD/PD) indicate overall response assessed by the Investigator per the criteria corresponding to the underlying tumor type.
  • the text (numbers) at the end of each row indicates PFS time, DoT, BOR, and death time.
  • the DoT was defined as the time interval from Day 1 to the date of last IV plus 6 days.
  • DC/CB/R at the end of each line indicates the DC response, CB response, or overall response.
  • FIG. 4 is a graph showing pharmacokinetics profiles of the tested doses of Compound I.
  • FIG. 5 depicts results showing Compound I-associated inhibition of CDK9 transcriptional target MYC.
  • FIG. 6 depicts results showing Compound I-associated inhibition of CDK9 transcriptional target MCL1.
  • FIG. 7 depicts results showing Compound I-associated inhibition of phosphorylation of PNAP2 at 2 hours in PBMCs.
  • compositions or processes as “consisting of and “consisting essentially of the enumerated ingredients/steps, which allows the presence of only the named ingredients/steps, along with any impurities that might result therefrom, and excludes other ingredients/steps.
  • the terms “about” and “at or about” mean that the amount or value in question can be the value designated some other value approximately or about the same. It is generally understood, as used herein, that it is the nominal value indicated ⁇ 10% variation unless otherwise indicated or implied. The term is intended to convey that similar values promote equivalent results or effects recited in the claims. That is, it is understood that amounts, sizes, formulations, parameters, and other quantities and characteristics are not and need not be exact, but can 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.
  • Compound 1, or a pharmaceutically acceptable salt thereof is administered to the subject in an amount of from 18 mg/m 2 .
  • Compound I is administered to the subject intravenously.
  • Compound I is administered once weekly.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction of oncogene transcription relative to pre-dose levels. In some aspects of the disclosed methods, administration of Compound I, or a pharmaceutically acceptable salt thereof, results in a dose-dependent reduction in oncogene transcription relative to pre-dose levels.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by 0.05-fold to 0.95-fold, such as, for example, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, or 0.95-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.05-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.1 -fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.15-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.2-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.25-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.3-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.35-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.4-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.45-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.5-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.55-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.6-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.65-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.7-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.75-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.8-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in oncogene transcription that is decreased relative to pre-dose levels by about 0.85-fold.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 20-60% relative to pre-dose levels.
  • p- RNAP2 RNA polymerase 2
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 30-80% relative to pre-dose levels.
  • p- RNAP2 RNA polymerase 2
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 30-70% relative to pre-dose levels.
  • p- RNAP2 RNA polymerase 2
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 40-50% relative to pre-dose levels.
  • p- RNAP2 RNA polymerase 2
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 27% relative to pre-dose levels.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 27% relative to pre-dose levels.
  • administration of Compound I, or a pharmaceutically acceptable salt thereof results in reduction in phosphorylation of RNA polymerase 2 (p- RNAP2) in the subject of 77% relative to pre-dose levels.
  • Aspect 2 The method of aspect 1, wherein the CDK9 inhibitor comprises Compound 1, or a pharmaceutically acceptable salt thereof.
  • Aspect 3 The method of any one of the preceding aspects, wherein the
  • CDK9 inhibitor is administered using a dosing regimen and schedule disclosed herein.
  • Aspect 4 The method of any one of the preceding aspects, wherein the transcriptionally active cancer comprises one or more transcriptional dependent cancers.
  • Aspect 5 The method of any one of the preceding aspects, wherein the transcriptionally active cancer comprises prostate cancer.
  • Aspect 6 The method of aspect 5, wherein the prostate cancer comprises castration-resistant prostate cancer.
  • Dose escalation employed a Bayesian optimal interval design to evaluate the safety, tolerability, and incidence of dose-limiting toxicities (DLTs).
  • Key exclusion criteria include:
  • the primary endpoint was to identify dose-limiting toxicities (DLTs) and establish the maximum tolerated dose and the recommended phase 2 dose (RP2D) of Compound I based on incidence of DLTs, adverse events (AEs), changes in laboratory parameters, and changes in dosing.
  • DLTs dose-limiting toxicities
  • R2D recommended phase 2 dose
  • Secondary endpoints include evaluation of the pharmacokinetic profde, safety, and efficacy signal of Compound I based on overall response rate, disease control rate, duration of response, and progression-free survival (PFS).
  • PFS progression-free survival
  • Exploratory endpoints include the pharmacodynamic assessment of the expression of CDK9 transcriptional targets (MYC, MCL1) in peripheral blood mononuclear cells (PBMCs) that may be associated with response to CDK9 inhibition. Phosphorylation of RNAP2 (p-RNAP2) was assessed by capillary electrophoresis and monitoring changes in absolute monocyte and neutrophil counts using clinical complete blood count.
  • MYC CDK9 transcriptional targets
  • PBMCs peripheral blood mononuclear cells
  • Compound I was administered (by intravenous infusion) once weekly for a three-week cycle.
  • qPCR was conducted using the PerfeCTa SYBR Green SuperMix kit (Cat. No. 95054).
  • a dose-dependent downregulation of MYC and MCL1 mRNA expression in PBMCs was observed (FIGS. 5 and 6, respectively). Maximum inhibition of CDK9 transcriptional targets MYC and MCL1 at doses >12 mg/m 2 is consistent with the degree of target engagement required for preclinical efficacy.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des procédés de réduction de la transcription oncogène, ou de réduction de l'ARN polymérase 2 phosphorylée, chez un sujet en ayant besoin par administration au sujet du composé (I), ou d'un sel pharmaceutiquement acceptable de celui-ci.
PCT/US2024/049630 2023-10-02 2024-10-02 Inhibiteurs de cdk et leur utilisation en tant que produits pharmaceutiques Pending WO2025076115A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363587166P 2023-10-02 2023-10-02
US63/587,166 2023-10-02

Publications (1)

Publication Number Publication Date
WO2025076115A1 true WO2025076115A1 (fr) 2025-04-10

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230242543A1 (en) * 2019-09-11 2023-08-03 Prelude Therapeutics Incorporated CDK Inhibitors And Their Use As Pharmaceuticals
US12486277B2 (en) * 2023-04-04 2025-12-02 Prelude Therapeutis Incorporated CDK inhibitors and their use as pharmaceuticals

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160376287A1 (en) * 2015-06-29 2016-12-29 Astrazeneca Ab Chemical Compounds
US20210070761A1 (en) * 2019-09-11 2021-03-11 Prelude Therapeutics Incorporated Cdk inhibitors and their use as pharmaceuticals
US20220267321A1 (en) * 2019-06-27 2022-08-25 Medshine Discovery Inc. Azaindole pyrazole compounds as cdk9 inhibitors
WO2023064920A1 (fr) * 2021-10-14 2023-04-20 Prelude Therapeutics Incorporated Formes cristallines d'un benzimidazole substitué agissant comme inhibiteur de cdk9 et leurs utilisations

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160376287A1 (en) * 2015-06-29 2016-12-29 Astrazeneca Ab Chemical Compounds
US20220267321A1 (en) * 2019-06-27 2022-08-25 Medshine Discovery Inc. Azaindole pyrazole compounds as cdk9 inhibitors
US20210070761A1 (en) * 2019-09-11 2021-03-11 Prelude Therapeutics Incorporated Cdk inhibitors and their use as pharmaceuticals
WO2023064920A1 (fr) * 2021-10-14 2023-04-20 Prelude Therapeutics Incorporated Formes cristallines d'un benzimidazole substitué agissant comme inhibiteur de cdk9 et leurs utilisations

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230242543A1 (en) * 2019-09-11 2023-08-03 Prelude Therapeutics Incorporated CDK Inhibitors And Their Use As Pharmaceuticals
US12486277B2 (en) * 2023-04-04 2025-12-02 Prelude Therapeutis Incorporated CDK inhibitors and their use as pharmaceuticals

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