MP34-04 A NEW GENERATION OF N-TERMINAL DOMAIN ANDROGEN RECEPTOR INHIBITORS IN CASTRATION-RESISTANT PROSTATE CANCER MODELS

Abstract

INTRODUCTION AND OBJECTIVES: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease. While the latest generation anti-androgens provide clinical benefits to CRPC patients, resistance linked with the ligand binding domain (LBD) inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit AR transcription even in the presence of anti-androgen resistance. A Phase I clinical trial of the first generation AR NTD inhibitor, EPI-506 (EPI-002 pro-drug), demonstrated PSA declines in anti-androgen resistant metastatic CRPC patients. However, these declines were minor and of short duration, revealing the need for more potent and metabolically stable NTD inhibitors. Next generation NTD inhibitors (anitens) have been developed and their characterization will be presented. METHOD(S): 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. RESULT(S): Next generation anitens, EPI-7170, EPI-7245 and EPI-7324, demonstrated a 10-70 fold improvement on ARdriven cellular potency when compared to the clinical compound EPI-002. While IC50s ranged from <500 nM and ~1 uM, for EPI- 7245 and EPI-7170 respectively, EPI-7324 diplayed potency <300 nM, similar to enzalutamide and bicalutamide. In vitro proliferation assays demonstrated on-target activity for these next-generation anitens, with an IC50 >5 fold higher in AR-independent PC-3 cells compared to AR-dependant LNCaP cells while also displaying activity in AR-V7-driven cellular models. While EPI-7170 exhibited ~ 70% tumor growth inhibition in castrated mice bearing LNCaP tumors, its ADME and PK profile were not optimal. More recent molecules, including EPI-7245 and EPI-7324, represent next generation aniten molecules with improved potency, selectivity, and metabolic stability compared to EPI-002 and EPI-7170. CONCLUSION(S): The next generation aniten compounds are 10-70 times more active than EPI-002 in cellular potency assays, predicted to be metabolically stable, and selectively inhibit AR transcription in anti-androgen resistant models. Their potential in overcoming anti-androgen clinical resistance to the current generation of anti-androgens will be discussed.