Next generation N-terminal domain androgen receptor inhibitors with improved potency and metabolic stability in castration-resistant prostate cancer models.

Abstract

220 Background: EPI-506, pro-drug of EPI-002, was a first-in-class oral small molecule from the Aniten family of compounds, which inhibit androgen receptor (AR) activity by binding to the N-terminal domain of the AR. EPI-506 was tested in a Phase 1 study in men with metastatic castration-resistant prostate cancer (mCRPC) resistant to current therapies and demonstrated a favorable tolerability profile with signs of moderate efficacy. Metabolic vulnerabilities in the chemical scaffold of EPI-506 were identified and new Aniten molecules, EPI-7170 and EPI-7245 , with improved potency, metabolic stability and pharmaceutical properties have been generated. Methods: Chemical structure activity relationships were developed in order to increase molecule potency in cellular and in vivo assays, while metabolic stability improvements were assessed in in vitro ADME assays and in animal pharmacokinetic studies. In addition, the on-target activity and selectivity was also optimized using a variety of cellular experiments. Results: Next generation Anitens demonstrated a 10-20 fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM when compared to 10-12 uM for EPI-002. In vitro proliferation assays demonstrated on target activity, with an IC50 ~ 2 uM in LNCaP and > 10 uM in the AR-independent cell model PC-3. EPI-7170 was also active in AR-V7-driven LNCaP95 cells. The antiproliferative effect was in alignment with the inhibitory effect on a subset of AR driven genes. In vivo activity in castrated mice bearing LNCaP tumors showed tumor growth inhibition of approximately 70%. While EPI-7170 represents a major advance, subsequent chemistry efforts led to the generation of EPI-7245 and other next generation Anitens which exhibit IC50’s < 500 nM and favorable ADME and PK profiles. Conclusions: Promising next-generation Aniten compounds have been identified. Major chemistry efforts led to the identification of several Anitens with > 10-20 fold improvements in cellular potency compared to EPI-506 which are also metabolically stable. IND-selection preclinical studies are underway on the most promising Aniten’s with an IND submission planned shortly.