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-10597354-B2
Publication Date
2020-03-24
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 selective androgen receptor degrader (SARD) compounds are represented by the structure of formula IA, wherein T, Z, Y, R, R1, R2, and Q1–Q5 are defined by specified substituent options and structural constraints. The compounds include at least two of Q1, Q2, Q3, Q4, and Q5 that are not hydrogens, or alternative embodiments in which 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 not dihydropyridin-2(1H)-one, pyridin-2(1H)-one, or 1H-pyrrole.
The compounds may be optical isomers, racemic mixtures, pharmaceutically acceptable salts, pharmaceutical products, polymorphs, hydrates, or any combination thereof. The methods administer these SARD compounds to treat hyperandrogenic hormonal conditions and specified cancers. A specific subset of the chemical scope is further described using formula III, together with additional ring-joining relationships and the same ring exclusions.
The invention addresses treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of hyperandrogenic hormonal conditions in a male in need thereof by administering a therapeutically effective amount of a SARD compound defined by formula IA. The invention also includes methods of treating prostate cancer and triple negative breast cancer in subjects in need thereof by administering the same class of SARD compounds having the specified formula IA.
Claims Coverage
The consolidated content includes three independent claims. Across these claims, the inventive coverage centers on administering therapeutically effective amounts of SARD compounds represented by formula IA to treat hyperandrogenic hormonal conditions, prostate cancer variants, and triple negative breast cancer, with structural definitions narrowing the chemical scope.
Formula IA selective androgen receptor degrader treatment for male hyperandrogenic conditions
Administering to a male subject in need thereof a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by formula IA, with defined substituent options for T, Z, Y, R, R1, R2, and Q1–Q5, including the requirement that at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogens or that Q groups are joined to form a substituted or unsubstituted C5–C8 carbocyclic or heterocyclic ring, where the formed ring is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole, and where the compound may be an optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or any combination thereof.
Prostate cancer treatment using formula IA SARD compounds for AR-related disease states
Treating prostate cancer in a subject in need thereof, wherein the subject has AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing prostate cancer, by administering a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by formula IA with the same defined substituent options and structural constraints for T, Z, Y, R, R1, R2, and Q1–Q5, including the requirement that at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogens or that Q1 and Q2, or Q2 and Q3, are joined to form a substituted or unsubstituted C5–C8 carbocyclic or heterocyclic ring that is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole, with permitted optical isomer, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combinations thereof.
Triple negative breast cancer treatment using a formula IA SARD
Treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of triple negative breast cancer in a subject in need thereof by administering a therapeutically effective amount of a selective androgen receptor degrader (SARD) compound represented by formula IA with defined substituent options and structural constraints for T, Z, Y, R, R1, R2, and Q1–Q5, including the requirement that at least two of Q1, Q2, Q3, Q4, and Q5 are not hydrogens or that Q1 and Q2, or Q2 and Q3, are joined to form a substituted or unsubstituted C5–C8 carbocyclic or heterocyclic ring that is not dihydropyridin-2(1H)-one, pyridin-2(1H)-one or 1H-pyrrole, with permitted optical isomer, racemic mixture, pharmaceutically acceptable salt, pharmaceutical product, polymorph, hydrate, or combinations thereof.
Across the independent claims, the inventive coverage is the administration of therapeutically effective amounts of formula-defined SARD compounds (formula IA) with specific substituent definitions, stereoisomer/salt/polymorph/hydrate allowances, and explicit exclusion of certain formed ring systems. The independent claims apply this SARD administration to male hyperandrogenic hormonal conditions, prostate cancer across AR-related clinical states, and triple negative breast cancer.
Stated Advantages
Allows antagonism of AR.
Induces degradation of AR-FL and AR splice variants (AR-SVs).
Treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of hyperandrogenic hormonal conditions in a male.
Treating prostate cancer in subjects with AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, or d567ES expressing prostate cancer.
Treating, suppressing, reducing the incidence, reducing the severity, or inhibiting the progression of triple negative breast cancer.
Documented Applications
Treatment of a hyperandrogenic hormonal condition in a male in need thereof.
Treatment of prostate cancer in a subject in need thereof, including AR overexpressing prostate cancer, castration-resistant prostate cancer, castration-sensitive prostate cancer, AR-V7 expressing prostate cancer, and d567ES expressing prostate cancer.
Treatment of triple negative breast cancer in a subject in need thereof.
Treating AR-expressing cancer, including hepatocellular carcinoma (HCC), salivary gland cancer, bladder cancer, melanoma, mantle cell lymphoma, renal cell carcinoma, non-small cell lung cancer (NSCLC), gastric cancer, and colon cancer.
Treating partial androgen insensitivity syndromes (PAIS) and gonadal tumors.
Treating seminoma and pre-cancerous lesions of the prostate, benign prostate hyperplasia, and prostate cancer.
Treating amyotrophic lateral sclerosis (ALS), abdominal aortic aneurysm (AAA), uterine fibroids, and wound/burn healing.
Topical dermatologic uses including hirsutism, androgenic alopecia, alopecia, acne/sebum reduction, and seborrheic dermatitis.
Pharmaceutical composition embodiments including topical pharmaceutical composition embodiments for the disclosed topical dermatologic uses.
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