Abstract 1292: A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models
Authors: Moigne Ronan Le , Mawji Nasrin R. , Banuelos C. Adriana , Wang Jun , Jian Kunzhong , Andersen Raymond J. , Sadar Marianne D. , Zhou Han-Jie , Virsik Peter 
Published: August 2019

Introduction: The androgen receptor (AR) pathway continues to drive castration-resistant prostate cancer (CRPC) even in late stages of the disease, and ligand binding domain (LBD)-linked resistance inevitably emerges. Selective inhibition of the N-terminal domain (NTD) of the AR can inhibit its’ 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. A new generation of NTD transcriptional inhibitors (Anitens) has been generated. Examples of this new class, EPI-7170 and EPI-7245, demonstrate improved potency, metabolic stability and pharmaceutical properties, and are potent against anti-androgen resistant prostate cancers in in vitro and in preclinical models.

Methods: Chemical structure activity relationships were developed to identify more potent molecules as measured by both 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 were also optimized using a variety of cellular experiments.

Results: These next generation Anitens demonstrated a 10-20-fold improvement on AR-driven cellular potency, with IC50’s of 0.5-1 uM compared to 10 uM for EPI-002. Aniten AR inhibition was specific to the NTD, as demonstrated by the absence of LBD binding and the inhibition of the AR-V7-driven transcription inLNCaP95 model. In vitro proliferation assays demonstrated AR-dependent activity, with an IC50 ~ 1 uM in LNCaP and &gt;10 uM in the AR-independent cell model PC-3. The antiproliferative effect aligned with the inhibitory effect on a subset of AR-driven genes. In vivo, next generation Anitens demonstrated PSA serum decreases along with significant tumor growth inhibition in mice bearing LNCaP tumors. 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 &lt;500 nM. These new compounds exhibited favorable ADME and PK profiles, with half-life ~ 8 hrs in mice, and predicted low human clearance.

Conclusions: Promising next-generation Aniten compounds have been identified which retain the NTD specificity of first-generation agents. These new molecules demonstrate major improvements in potency and metabolic stability in comparison to the first-generation clinical compound EPI-002. These next generation Anitens, by selectively inhibiting AR transcription in both hormone sensitive and castrated resistant prostate cancer, represent an important next step in AR targeted therapeutics.

Citation Format: Ronan Le Moigne, Nasrin R. Mawji, C. Adriana Banuelos, Jun Wang, Kunzhong Jian, Raymond J. Andersen, Marianne D. Sadar, Han-Jie Zhou, Peter Virsik. A new generation of N-terminal domain androgen receptor inhibitors, with improved pharmaceutical properties, in castration-resistant prostate cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1292.