2. Academic Validation
  3. Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally Available RORγ Inverse Agonist

Discovery and Characterization of Benzimidazole Derivative XY123 as a Potent, Selective, and Orally Available RORγ Inverse Agonist

  • J Med Chem. 2021 Jun 24;64(12):8775-8797. doi: 10.1021/acs.jmedchem.1c00763.
Xishan Wu 1 2,  Hui Shen 1 3,  Yan Zhang 1 2,  Chao Wang 1 3,  Qiu Li 1 3,  Cheng Zhang 1,  Xiaoxi Zhuang 1,  Chenchang Li 1,  Yudan Shi 1,  Yanli Xing 1,  Qiuping Xiang 1,  Jinxin Xu 4,  Donghai Wu 4,  Jinsong Liu 5,  Yong Xu 1 2 5
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Biocomputing, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou 510530, China.
  • 2 Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou 510005, China.
  • 3 University of Chinese Academy of Sciences, No. 19 Yuquan Road, Beijing 100049, China.
  • 4 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 5 State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
PMID: 34121397 DOI: 10.1021/acs.jmedchem.1c00763
Abstract

Receptor-related Orphan Receptor γ (RORγ) has emerged as an attractive therapeutic target for the treatment of Cancer and inflammatory diseases. Herein, we report our effort on the discovery, optimization, and evaluation of benzothiazole and benzimidazole derivatives as novel inverse agonists of RORγ. The representative compound 27h (designated as XY123) potently inhibited the RORγ transcription activity with a half-maximal inhibitory concentration (IC50) value of 64 nM and showed excellent selectivity against Other nuclear receptors. 27h also potently suppressed cell proliferation, colony formation, and the expression of Androgen Receptor (AR)-regulated genes in AR-positive prostate Cancer cell lines. In addition, 27h demonstrated good metabolic stability and a pharmacokinetic property with reasonable oral bioavailability (32.41%) and moderate half-life (t1/2 = 4.98 h). Significantly, oral administration of compound 27h achieved complete and long-lasting tumor regression in the 22Rv1 xenograft tumor model in mice. Compound 27h may serve as a new valuable lead compound for further development of drugs for the treatment of prostate Cancer.

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