Inhibitors of the N-terminal domain of the androgen receptor
Inventors
Rettig, Matthew • Jung, Michael E. • Ralalage, D. Elshan Nakath G. • An, Jiabin
Assignees
US Department of Veterans Affairs • University of California San Diego UCSD
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Publication Number
US-11261152-B2
Publication Date
2022-03-01
Expiration Date
2038-01-19
Abstract
The present disclosure provides compounds and methods for inhibiting or degrading the N-terminal domain of the androgen receptor, as well as methods for treating cancers such as prostate cancer.
Core Innovation
The invention provides compounds and methods for inhibiting or degrading the N-terminal domain of the androgen receptor (AR), specifically targeting the AR transactivation domain (TAD). These compounds include a range of chemical structures defined by formulas I through VIII, with specific substituents and configurations that confer selective AR inhibitory activity. The compounds methodically affect AR transcriptional activity and enhance AR degradation, offering a novel mechanism of action against prostate cancer.
Prostate cancer, particularly castration resistant prostate cancer (CRPC), remains a clinical challenge due to persistent AR expression and activity despite existing androgen deprivation therapies that primarily target the AR ligand binding domain (LBD). Resistance emerges because current therapies fail to inhibit constitutively active AR splice variants lacking a functional LBD. This invention addresses the unmet need for improved AR inhibitors that target the N-terminal TAD, thereby inhibiting both full-length AR and splice variants, and inducing degradation of the AR protein.
Claims Coverage
The patent includes one independent claim covering a specific compound structure, with additional claims addressing compositions and methods of use. The inventive features focus on the chemical structure, pharmaceutical compositions, and therapeutic methods involving AR inhibition and degradation.
Compounds targeting AR N-terminal domain
Provides compounds represented by formula VIIb with defined substituents R8 and R9 (halo groups), and specific integer values for t and q (1, 2 or 3). These compounds are designed to inhibit or degrade the androgen receptor by targeting the N-terminal transactivation domain.
Pharmaceutical compositions of the compounds
Claims pharmaceutical compositions comprising the compound defined in formula VIIb along with pharmaceutically acceptable excipients suitable for administration.
Method of androgen receptor inhibition
Claimed methods include inhibiting androgen receptor activity by contacting the receptor with the compound of formula VIIb, representing a novel mechanism of AR inhibition targeting the N-terminal domain.
Method of inducing androgen receptor degradation
Includes methods of inducing degradation of the androgen receptor by contacting it with the compound of formula VIIb, which promotes degradation of both full-length receptor and splice variants.
Method of treating prostate cancer
Claims treatment methods for prostate cancer by administering the compound of formula VIIb to a mammal in need thereof, including resistant and castration resistant forms of prostate cancer.
The claims collectively cover novel compounds targeting the AR N-terminal domain, pharmaceutical compositions containing these compounds, and methods for inhibiting AR activity, inducing AR degradation, and treating prostate cancer using these compounds.
Stated Advantages
Targets the androgen receptor N-terminal transactivation domain, including full-length AR and constitutively active splice variants lacking a functional ligand binding domain.
Induces degradation of the androgen receptor including splice variants, providing a mechanism not offered by current AR-targeting therapies.
Selective inhibition of AR transactivation without affecting closely related receptors such as glucocorticoid receptor, reducing off-target effects.
Demonstrates inhibitory effects on growth of AR-expressing prostate cancer cells, including treatment-resistant and castration-resistant forms, suggesting therapeutic potential in advanced prostate cancer.
Compounds exhibit improved activity profiles and reduced toxicity compared to existing therapies in preclinical models, with demonstrated efficacy in vivo in mouse xenograft models.
Documented Applications
Treatment of prostate cancer, including castration resistant prostate cancer (CRPC) and metastatic and non-metastatic forms.
Treatment of prostate cancer resistant to antiandrogen therapies such as enzalutamide, bicalutamide, abiraterone, flutamide, nilutamide, and combination therapies including abiraterone acetate with prednisone.
Use as AR inhibitors and degraders in the management of AR-dependent diseases driven by AR and its splice variants.
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