Development of an Androgen Receptor Inhibitor Targeting the N-Terminal Domain of Androgen Receptor for Treatment of Castration Resistant Prostate Cancer

SIMPLE SUMMARY: In almost all patients, the proliferation and growth of prostate cancer is driven by the androgen receptor. Given this critical role, inhibiting the androgen receptor is the standard of care following surgery or radiotherapy. However, the effectiveness of current anti-androgen therapeutics is almost always temporary, with the cancer eventually developing drug resistance. There are no curative treatment options for resistant prostate cancer and these patients have an average life-expectancy of only 20 months. Currently, all clinical inhibitors of the androgen receptor act by direct binding to the hormone binding site. These drugs are therefore vulnerable to mutations which frequently arise at this region or to the emergence of truncated forms of the androgen receptor that are constitutively active without any need of hormone binding. In this study, we aim to develop small molecules inhibitors that attack the molecular functions of the androgen receptor at the N-terminal domain, distinct from steroid recruitment to evade resistance to conventional treatments. ABSTRACT: Prostate cancer patients undergoing androgen deprivation therapy almost invariably develop castration-resistant prostate cancer. Resistance can occur when mutations in the androgen receptor (AR) render anti-androgen drugs ineffective or through the expression of constitutively active splice variants lacking the androgen binding domain entirely (e.g., ARV7). In this study, we are reporting the discovery of a novel AR-NTD covalent inhibitor 1-chloro-3-[(5-([(2S)-3-chloro-2-hydroxypropyl]amino)naphthalen-1-yl)amino]propan-2-ol (VPC-220010) targeting the AR-N-terminal Domain (AR-NTD). VPC-220010 inhibits AR-mediated transcription of full length and truncated variant ARV7, downregulates AR response genes, and selectively reduces the growth of both full-length AR- and truncated AR-dependent prostate cancer cell lines. We show that VPC-220010 disrupts interactions between AR and known coactivators and coregulatory proteins, such as CHD4, FOXA1, ZMIZ1, and several SWI/SNF complex proteins. Taken together, our data suggest that VPC-220010 is a promising small molecule that can be further optimized into effective AR-NTD inhibitor for the treatment of CRPC.