Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men in the United States. Androgen deprivation therapy (ADT) through surgical or chemical castration is the mainstay of therapy for patients with metastatic PCa. The androgen receptor (AR) plays a central role in the progression of this disease. The AR has three distinct regions in its structure; a N-terminal transactivation domain (TAD), a DNA binding domain (DBD), and a ligand binding domain (LBD). ADT and all current AR antagonists function by directly or indirectly targeting the AR–LBD which inhibits PCa progression. Patients eventually develop resistance to these current therapies, leading to the lethal form of PCa termed metastatic castration-resistant prostate cancer (mCRPC). Primary resistance mechanisms involve but are not limited to 1) LBD mutations and 2) the evolution of constitutively active AR splice variants that lack a functional LBD. Given that the primary resistance mechanisms are centered upon the AR–LBD, there is an unmet need to develop therapies that target the other functional domains on the AR. Here, we show the targeting of CRPC through a novel class of AR inhibitors that target the AR–TAD and also enhance the degradation of AR protein. These compounds have shown excellent in vitro and in vivo characteristics in inhibiting AR-driven CRPC tumor growth. Given the promising ability to inhibit the AR signaling axis even in the presence of constitutively active AR splice variants, these compounds are currently being further-developed as potential therapeutics for the treatment of CRPC.

Androgen receptor degraders and transactivation domain inhibitors targeting castration-resistant prostate cancer

2019 Spring National Meeting

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