Novel Selective Agents for the Degradation of Androgen Receptor Variants to Treat Castration-Resistant Prostate...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Androgen receptor (AR) signaling drives prostate cancer progression, including castration-resistant disease mediated by AR splice variants (AR-SV).
• Unlike other steroid receptors, AR is stabilized by androgens, complicating therapeutic targeting.
• Effective treatment for advanced prostate cancer requires agents that can degrade AR and its variants.

Purpose of the Study:

• To discover and characterize novel potent selective androgen receptor degraders (SARDs).
• To evaluate the efficacy of SARDs against wild-type and variant AR isoforms in advanced prostate cancer.

Main Methods:

• Discovery and characterization of three SARDs: UT-69, UT-155, and (R)-UT-155.
• Assessment of SARDs' binding to AR amino-terminal (AF-1) and carboxy-terminal ligand-binding domains.
• Evaluation of AR degradation and functional inhibition by SARDs at submicromolar concentrations.

Main Results:

• SARDs (UT-69, UT-155, (R)-UT-155) potently reduced wild-type and variant AR activity at submicromolar doses.
• SARDs bind to the AR AF-1 domain, a novel degradation target, with some also binding the ligand-binding domain.
• All tested SARDs degraded wild-type AR and inhibited AR function more effectively than current AR antagonists.

Conclusions:

• The discovered SARDs represent a promising new class of therapeutics for advanced prostate cancer.
• Targeting the AR AF-1 domain offers a novel strategy for AR degradation.
• SARDs demonstrate superior potency compared to existing AR antagonists, offering a potential next-generation treatment option.