Selective androgen receptor degrader (SARD) ligands and methods of use thereof
Inventors
Narayanan, Ramesh • Miller, Duane D. • Ponnusamy, Thamarai • Hwang, Dong-Jin • Duke, Charles B. • Coss, Christopher C. • JONES, Amanda • Dalton, James T.
Assignees
University of Tennessee Research Foundation • Oncternal Therapeutics Inc
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Publication Number
US-11591290-B2
Publication Date
2023-02-28
Expiration Date
Abstract
This invention provides novel 3-amino propanamide selective androgen receptor degrader (SARD) compounds, pharmaceutical compositions and uses thereof in treating prostate cancer, advanced prostate cancer, castration resistant prostate cancer, androgenic alopecia or other 5 hyperandrogenic dermal diseases, Kennedy's disease, amyotrophic lateral sclerosis (ALS), and uterine fibroids, and to methods for reducing the levels of androgen receptor-full length (AR-FL) including pathogenic or resistance mutations, AR-splice variants (AR-SV), and pathogenic polyglutamine (polyQ) polymorphisms of AR in a subject.
Core Innovation
The invention relates to a method for treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition in a subject in need thereof. The method comprises administering to a subject in need thereof a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by formula IA. The formula IA is defined by variable substituents T, Z, Y, R, R1, R2, Q1, Q2, Q3, Q4, and Q5 with extensive allowed options for each substituent.
The structural scope includes embodiments where at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogens, and where Q1 and Q2 or Q2 and Q3 are joined to form a substituted or unsubstituted C5-C8 carbocyclic or heterocyclic ring. The formed carbocyclic or heterocyclic ring is explicitly excluded from being dihydropyridin-2(1H)-one, pyridin-2(1H)-one, or 1H-pyrrole. The compound class includes optical isomers, racemic mixtures, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, hydrates, or any combination thereof.
The SARD compounds are described as androgen receptor antagonists that bind AR beyond and/or at an alternate binding and degradation domain in the N-terminal region in addition to, or instead of, the ligand-binding domain. This mechanism is described as leading to degradation of AR full length and AR splice variants, including AR-V7 and ARv567es/AR-V12, and as providing activity against antiandrogen-resistant AR mutants, including AR-LBD mutations such as W741L and T877A.
Claims Coverage
The independent claim coverage is directed to a method of treating or inhibiting the progression of an androgen-dependent disease or condition using a selective androgen receptor degrader (SARD) compound having formula IA with specified substituent constraints, allowed pharmaceutical forms, and explicit exclusions of certain ring types. Dependent claims further narrow the structural embodiment to formula III, fixed substituents such as Q1 = CN, specific ring-joining relationships, and illustrated or specifically shown chemical structures.
Formula IA SARD method for androgen-dependent conditions
A method of treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition by administering to a subject a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by formula IA, with defined substituents T, Z, Y, R, R1, R2, Q1, Q2, Q3, Q4, and Q5, with at least two of Q1-Q5 not hydrogens, and with optional optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
Joined Q1 and Q2 or Q2 and Q3 ring embodiments
Embodiments where Q1 and Q2 or Q2 and Q3 are joined to form a substituted or unsubstituted C5-C8 carbocyclic or heterocyclic ring, while excluding formed rings that are dihydropyridin-2(1H)-one, pyridin-2(1H)-one, or 1H-pyrrole.
Formula III structural embodiment
A narrowed embodiment where the administered SARD compound is represented by formula III.
Q1 is CN substituent constraint
A further limitation in which Q1 is CN.
Q2 and Q3 joined to form a C5-C8 non-aromatic ring
A further limitation in which Q2 and Q3 are joined to form a substituted or unsubstituted C5-C8 non-aromatic carbocyclic ring or a substituted or unsubstituted C5-C8 heterocyclic ring.
Illustrated or specifically shown compound structures
Use of a compound defined by any one of the illustrated compound structures or by the specific chemical structure shown in the provided images.
Coverage centers on administering formula IA SARD compounds, including joined C5-C8 carbocyclic or heterocyclic ring embodiments and permitted pharmaceutical forms, to treat or inhibit progression of androgen-dependent diseases or conditions. Dependent claims further narrow the compounds by formula III, fixed substituents, and illustrated or specifically shown structures.
Stated Advantages
Treating, suppressing, reducing the incidence of, reducing the severity of, or inhibiting the progression of an androgen-dependent disease or condition.
Reducing androgen receptor species including AR, AR-FL, AR-LBD mutation variants, AR splice variants, and gene-amplified AR.
The compounds are positioned as selective androgen receptor degrader (SARD) compounds for therapy of androgen-dependent diseases or conditions.
The mechanism is described as providing degradation of AR full length and AR splice variants, including AR-V7 and ARv567es/AR-V12.
The compounds are described as providing activity against antiandrogen-resistant AR mutants, including AR-LBD mutations such as W741L and T877A.
Topical versus systemic use may be advantageous.
Documented Applications
Treatment of prostate cancer, including advanced prostate cancer and castration resistant prostate cancer (CRPC), including metastatic CRPC and non-metastatic CRPC, including higher-risk non-metastatic CRPC.
Treatment of androgen-dependent conditions including hypergonadism, hypersexuality, sexual dysfunction, gynecomastia, precocious puberty in a male, hair loss, hyperandrogenic dermatological disorders, pre-cancerous lesions of the prostate, and benign prostate hyperplasia.
Use for other androgen-dependent cancers.
Use in contexts involving AR-FL and/or AR splice variants proliferation.
Use with androgen deprivation therapy (ADT) and after failure of ADT and antiandrogen resistance, including enzalutamide and other named AR antagonists.
Broad use beyond prostate cancer by referencing hormonal androgen-receptor associated conditions, including Kennedy’s disease (SBMA).
Prostate cancer, including advanced/metastatic CRPC.
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