Proxalutamide (Gt0918), A Potent Androgen Receptor Pathway Inhibitor

Elevated AR expression or mutations in tumor cells, causing resistance to first generation AR antagonist agents, are considered the main driver of castration resistant prostate cancer (CRPC). MDV3100, a more potent AR antagonist ( 5x vs bicalutamide) without residual agonism, has demonstrated excellent efficacy in CRPC patients and has been approved by FDA for treating CRPC in clinic. More recently, AR antagonists demonstrated anti-tumor activities in preclinical AR+ breast cancer models and are being tested in clinical trials. Although MDV3100 is generally well-tolerated, there is a need to eliminate the clinically observed CNS AE9s ( 1% incidences of seizure) and revserse the resistance to MDV3100 in CRPC patients. Suzhou Kintor previously reported a preclinical candidate compound Proxalutamide (GT0918), a potent androgen receptor (AR) antagonist with ability to down regulate AR protein level in prostate cancer cells. In biochemical assay, GT0918 more potently inhibits androgen binding with AR9s ligand binding domain than Bicalutamide (11.4x) and MDV3100(3.5x). In both hormone-sensitive (LNCaP) and CRPC (C4-2) cancer cells, GT0918 demonstrated stronger potency to block AR function of gene transcription than Bicalutamide (∼5-10) and MDV3100(2-5x) while maintaining full antagonism in CRPC cells. GT0918 impairs androgen stimulated AR translocation to cell nuclei hence blocks its binding DNA and shuts down the downstream oncogenic signaling. Moreover, GT0918 induced AR down regulation in prostate cancer cells. As the AR up-regulation remains to be the main driver of CRPC resistance, its feature of AR down regulation may enable GT0918 to retain efficacy against CRPC that have developed resistance to current AR-blockage treatments. In vitro, GT0918 not only inhibits proliferation of hormone-sensitive CaP cells, but also more potently inhibits proliferation of CRPC cells than MDV3100 (6.5x). In addition, GT0918 inhibits the growth of AR positive breast cancer cells. In contrast, GT0918 has minimum effects on the growth of AR-negative CaP cells (PC-3 and DU145), indicating it is a selective AR pathway inhibitor. In vivo, GT0918 demonstrated good anti-tumor efficacy among hormone sensitive, CRPC and AR+ breast cancer animal models with efficacious drug exposure lower than MDV3100. ADME profile was optimized for once a day dosing schedule in human to reduce drug accumulation as seen in MDV3100. IND-enabling GLP toxicology studies have been completed for GT0918, which was well-tolerated with minimum safety findings except for the effects expected from anti-androgens. Toxicokinetic studies confirmed the drug exposures in toxicology studies were significantly higher (rat: 11; dog: 25x) than the exposure required for maximum efficacy. No seizure was observed across all the animal safety studies. An IND application has been filed for starting Phase I clinical trial to test the selective AR pathway blocker GT0918 in patients. Citation Format: Youzhi Tong, Chunyun Chen, Juan Wu, Jiangtao Yang, Huihui Zhang, Xiaojun Wu, Yanmei Duan, Wei Gao, Weidong Qian, Xiaoxia Niu, Lili Mi, Chuangxing Guo. Proxalutamide (GT0918), a potent androgen receptor pathway inhibitor. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 614. doi:10.1158/1538-7445.AM2014-614