Abstract 429: Androgen receptor (AR) N-terminal domain degraders can degrade AR full length and AR splice variants in CRPC preclinical models
Authors: Hong Nan Hyung , Biannic Berenger , Virsik Peter , Zhou Han-Jie , Moigne Ronan Le 
Published: June 2022

Introduction: Androgen receptor (AR) signaling is a main driver of prostate cancer progression and remains a crucial target for therapeutic intervention even in late stages of the disease. Current antiandrogen therapies directly or indirectly target the AR ligand binding domain (LBD) and are initially effective in prostate cancer patients. However, resistance ultimately develops, and new methods of inhibiting the AR pathway are needed. The selective targeting of the N-terminal domain (NTD) of the AR by small molecule anitens represents a novel method of blocking AR signaling that can bypass LBD-related resistance mechanisms. AR NTD is an intrinsically disordered region (IDR) which has no stable ordered structure and is generally regarded as an undruggable target due to the lack of a well-defined small-molecule binding pocket. However, we recently demonstrated that EPI-7386, an AR NTD small molecule inhibitor, inhibits AR activity by binding to Tau5 region of the NTD. By developing an aniten based bifunctional degrader (ANITAC for ANITen bAsed Chimera), our goal is to eliminate any forms of AR protein found in castration-resistant prostate cancer (CRPC), that can potentially drive disease progression, including LBD mutants and AR truncated variants.

Methods: AR degradation was monitored by Western Blot or by using the HiBit assay. AR transcriptional activity was measured using different reporter assays following AR full length (FL) or truncated AR activity in in vitro models.

Results: Here we report the first series of AR degraders targeting the NTD of AR, which lead to degradation of all forms of AR, including AR-V7 and AR-v567es. ANITACs eliminate AR in all cell lines tested through an E3 ligase dependent mechanism, with an observed 50% degradation concentration (DC50) &lt; 20 nM in 22Rv1 cells for the most potent compounds. AR degradation mediated by ANITACs suppresses the expression of AR target genes and decreases the viability of prostate cancer cells. ANITACs also degrade clinically relevant AR mutants and AR splice variants and show inhibition of AR transcriptional activity in multiple cell lines expressing different forms of AR including AR FL (LNCaP, CWR-AD1), AR-V7 (22Rv1), AR-V567es (CWR-D567). In vitro and in vivo PK studies show the compounds are metabolically stable and exhibit excellent oral bioavailability in mice.

Conclusion: In summary, we report preclinical data on the first generation of ANITAC molecules, that can be orally bioavailable and show activity against forms of AR expressed in late stage CRPC patients.

Citation Format: Nan Hyung Hong, Berenger Biannic, Peter Virsik, Han-Jie Zhou, Ronan Le Moigne. Androgen receptor (AR) N-terminal domain degraders can degrade AR full length and AR splice variants in CRPC preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 429.