Abstract 2460: Discovery of potent androgen receptor antagonists for treating CRPC and AR+ breast cancer.
Authors: Tong Youzhi , Chen Chunyun , Wu Juan , Zhang Huihui , Wu Xiaojun , Duan Yanmei , Gao Wei , Niu Xiaoxia , Ma Linglan , Guo Chuangxing 
Published: August 2014

Androgen Receptor (AR) antagonists have been used in clinic to treat prostate cancer. One example is bicalutamide (Casodex®), which is used along with castration to treat advanced prostate cancer. Unfortunately, the patients developed resistance to bicalutamide (alone or in combination therapy) after only 0.5-2 years of treatment, resulting in castration-resistant prostate cancer (CRPC). Elevated AR expression in tumor cells correlates with a change in the functional activity of bicalutamide from antagonist to agonist, suggesting that prostate tumors may adapt to survive on any residual agonism. 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. Recently, AR antagonists demonstrated anti-tumor activities in preclinical AR+ breast cancer models. Approximately 75% of invasive breast cancers were founded to be AR+.

Although MDV3100 is generally well-tolerated, there is a need to eliminate the clinically observed CNS adverse side effects (∼1% incidences of seizure). Suzhou Kintor launched a research effort looking for more potent full AR antagonists with reduced CNS drug distribution.

Lead series was rapidly generated by computer-aided drug design. Designed molecules based on clinically proven thiohydantoin core were docked into AR LBD binding site and filtered with criteria of binding and ability to induce antagonism conformation. Initial optimization mainly focused on improving AR antagonism potency. Additional substitutions were introduced in the left hand side to increase binding affinity to AR whereas more extended fragment was used in the AR helix 12 region to prevent AR to adopt agonism conformation hence ensure full antagonism (which may help overcome resistance arise from residual AR agonism). Further optimization for ADME properties with focus to reduce CNS drug exposure led to discovery of several candidate compounds, after overcoming the challenge of increase polarity while maintaining/improving AR antagonism potency. GT0918 and GT0903 emerged as two of top candidates for further preclinical clinical development. Both compounds have excellent affinity with AR (4-10x tighter than MDV3100), as well as potent AR antagonism (2-5x more potent than MDV3100). They also demonstrated good anti-tumor efficacy in both hormone sensitive and CRPC animal models. In addition, both candidate compounds demonstrated anti-proliferation effects in AR positive breast cancer cell lines (MCF-7 and MDA-MB-453). With higher polar surface area (PSA), GT0918 demonstrated low CNS drug distribution and no seizure was observed in animal toxicity studies (up to 1g/kg, rat/dog). With improved ADME profile (better solubility and predicted to have less drug accumulation in patients), GT0918 is being developed for Phase I trial start.

Citation Format: Youzhi Tong, Chunyun Chen, Juan Wu, Huihui Zhang, Xiaojun Wu, Yanmei Duan, Wei Gao, Xiaoxia Niu, Linglan Ma, Chuangxing Guo. Discovery of potent androgen receptor antagonists for treating CRPC and AR+ breast cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2460. doi:10.1158/1538-7445.AM2013-2460