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-12162818-B2
Publication Date
2024-12-10
Expiration Date
2038-01-19
Abstract
The present disclosure provides compounds of Formula (VIIb) 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 of Formula (VIIb) and related formulas, along with methods for inhibiting or degrading the N-terminal domain of the androgen receptor (AR). These compounds are used in treating cancers, notably prostate cancer. The compounds are characterized by various substituents defined in the formulas, enabling selective targeting of the AR's N-terminal transactivation domain (TAD).
The problem addressed arises from the limitations of current therapies for prostate cancer, especially castration-resistant prostate cancer (CRPC). CRPC is associated with persistent AR expression and transcriptional activity despite androgen deprivation therapies. Existing AR inhibitors target the ligand-binding domain (LBD) of the AR but fail to inhibit constitutively active AR splice variants lacking a functional LBD, leading to therapeutic resistance. There is a critical need for improved AR inhibitors capable of overcoming resistance by targeting other AR domains, such as the N-terminal domain.
Claims Coverage
The patent describes one independent claim directed to a compound with specific structural features and its use in pharmaceutical compositions and methods.
Compounds targeting the androgen receptor N-terminal domain
Compounds of formula VIIb, or pharmaceutically acceptable salts thereof, characterized by specific substituents (R8 and R9 independently selected from halogens such as fluoro or chloro), and variables t and q being 1 or more. These compounds selectively inhibit or degrade the AR by targeting its N-terminal TAD.
Pharmaceutical compositions comprising the compounds
Pharmaceutical compositions comprising a compound of formula VIIb or its salt together with pharmaceutically acceptable excipients suitable for administration.
Methods of inhibiting the androgen receptor
Methods of inhibiting AR by contacting the AR with a compound of formula VIIb or the pharmaceutical composition thereof.
Methods of inducing AR degradation
Methods of inducing degradation of the AR by contacting it with a compound of formula VIIb or composition thereof.
Methods of treating prostate cancer
Methods of treating a mammal with prostate cancer, including castration-resistant prostate cancer, by administering a compound of formula VIIb or its pharmaceutical composition.
The independent claim covers compounds of formula VIIb with defined substituents, pharmaceutical compositions comprising these compounds, and methods of inhibiting or degrading the AR, as well as treating prostate cancer using these compounds and compositions.
Stated Advantages
The compounds directly target the AR N-terminal transactivation domain, an unexplored therapeutic target that enables inhibition of full-length and splice variant ARs that lack a functional LBD.
These compounds induce degradation of AR and its splice variants, a mechanism not known for any AR targeting agent with regulatory approval.
The compounds exhibit selective cytoreductive effects on AR-expressing prostate cancer cells, inhibiting growth in models that are resistant to current therapies such as enzalutamide and abiraterone acetate.
Compounds demonstrate potent inhibition of AR-driven gene expression and tumor growth in castration-resistant prostate cancer models, with some analogues showing improved efficacy and reduced off-target effects.
Documented Applications
Treatment of cancers, particularly prostate cancer, including castration-resistant prostate cancer and metastatic and non-metastatic forms.
Treatment of cancers resistant to antiandrogen therapies such as enzalutamide, bicalutamide, abiraterone, flutamide, nilutamide, and combination treatments involving abiraterone acetate and prednisone.
Use in pharmaceutical compositions for therapeutic administration via various routes including oral, parenteral, and topical administration to inhibit AR activity or induce AR degradation in affected patients.
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