Prostate cancer is the second leading cause of mortality in men. The androgen receptor (AR) plays a central role in the progression of this disease. Androgens such as dihydrotestosterone bind the AR ligand binding domain (LBD) and activate the transcription of androgen dependent genes. Androgen deprivation therapy (ADT) through surgical or chemical castration is the mainstay of therapy for patients with metastatic prostate cancer. ADT and AR antagonists function by directly or indirectly targeting the AR ligand binding domain (LBD), which inhibits proliferation and survival. ADT results in responses in the vast majority of men, but virtually all patients will develop resistance at which point the disease is termed metastatic castration resistant prostate cancer (mCRPC). The metastatic castration resistant state accounts for the lethality attributable to prostate cancer. In the current work, we show the targeting of castration resistant prostate cancer (CRPC) through a novel class of AR signaling axis inhibitors that target the N-terminal transactivation domain of the AR. Having shown the ability to inhibit the AR signaling axis even in the presence of constitutively active AR splice variants that lack a function LBD and the ability to function as AR degraders, these compounds hold potential to be developed further for the treatment of CRPC.

Synthesis and evaluation of a novel class of androgen receptor signaling axis inhibitors targeting castration-resistant prostate cancer

253rd National Meeting (2017)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.