Abstract 3861: Proxalutamide (GT0918), a novel androgen receptor (AR) antagonist, targeting resistance mechanisms to AR signaling-directed castration-resistant prostate cancer (CRPC) therapies
Authors: Ma Liandong , Zhou Qianxiang , He Yang , Chen Jie , Zhou Karl , Zhou Qingqing , Chen Chunyun , Xiang Jason Shaoyun , Deng Xiaobing , Lai Luhua , Tong Youzi 
Published: August 2019

Abstract
Reactivation of androgen receptor (AR) plays a key role in prostate cancer growth, especially in castration-resistant prostate cancer (CRPC) progression. Accumulated data have demonstrated that the AR reactivation is resulted from AR amplification, AR overexpression and mutations in AR ligand binding domain (LBD) as well as AR splicing variants (AR-V7). This AR reactivation also drives the resistance to AR targeted therapies, including 1st and 2nd generations of AR antagonists, such as Bicalutamide (Bica) and Enzalutamide (Enza, MDV3100). Therefore, the development of novel and effective AR antagonists is in urgent need for overcoming AR reactivation for patients with metastatic castration-resistant prostate cancer (mCRPC).
Here we report a novel AR binding pose of Proxalutamide (GT0918), an AR antagonist, in silico of drug’s mode of action. We also reveal the effects of GT0918 on the transactivation of the wild type AR (wtAR) and AR mutants with comparisons to 1st and 2nd generations of AR antagonists (Bicalutamide and Enzalutamide). GT0918 was reported to have higher binding affinity than Bica (11.4X) and Enza (3.5X) in AR ligand binding assays previously. To gain detail insights into the mode of action of GT0918 and Enza in AR LBD, structure-based computer modeling was performed. The mode of drug action shows that GT0918 binds to AR LBD pocket. This compound not only fits in the AR LBD pocket very well, but also its structure pushes AR Helix 12 away, resulting in the decreased interaction between AR Helix 12 and LBD pocket, which creates a unique and significant difference from other AR blockers. GT0918 was further assessed in luciferase-based AR transactivation assays. The results showed GT0918 significantly inhibited the androgen-induced transactivation of the wtAR. Importantly, it also blocked the transcriptional activity of tested mutant ARs arising to targeted AR therapies, including the AR mutant F877L that converts the Enzalutamide and Apalutamide (ARN-509) from antagonist to agonist activity. In clinical trial setting, some mCRPC patients progressed on Enzalutamide and bicalutamide showed stable disease and durable responses after received GT0918 from various doses. In conclusion, our results support the clinical development of GT0918 in prostate cancer patients who progressed on Enzalutamide or/and AR blockers.
Citation Format: Liandong Ma, Qianxiang Zhou, Yang He, Jie Chen, Karl Zhou, Qingqing Zhou, Chunyun Chen, Jason Shaoyun Xiang, Xiaobing Deng, Luhua Lai, Youzi Tong. Proxalutamide (GT0918), a novel androgen receptor (AR) antagonist, targeting resistance mechanisms to AR signaling-directed castration-resistant prostate cancer (CRPC) therapies [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 3861.