2. Academic Validation
  3. Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

Discovery and Characterization of XY101, a Potent, Selective, and Orally Bioavailable RORγ Inverse Agonist for Treatment of Castration-Resistant Prostate Cancer

  • J Med Chem. 2019 May 9;62(9):4716-4730. doi: 10.1021/acs.jmedchem.9b00327.
Yan Zhang 1 2 3,  Xishan Wu 1 2 3,  Xiaoqian Xue 1 4,  Chenchang Li 1,  Junjian Wang 5,  Rui Wang 1,  Cheng Zhang 1 6,  Chao Wang 1 2 3,  Yudan Shi 1 2 3,  Lingjiao Zou 1 2 3,  Qiu Li 1 2 3,  Zenghong Huang,  Xiaojuan Hao 7,  Kerry Loomes 8,  Donghai Wu 9,  Hong-Wu Chen,  Jinxin Xu 9,  Yong Xu 1 3
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 University of Chinese Academy of Sciences , No. 19 Yuquan Road , Beijing 100049 , China.
  • 3 Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL) , Guangzhou 510530 , China.
  • 4 School of Life Science , Huizhou University , Huizhou 516007 , China.
  • 5 School of Pharmaceutical Sciences , Sun Yat-Sen University , Guangzhou 510006 , China.
  • 6 School of Pharmaceutical Sciences , Jilin University , No.1266 Fujin Road , Chaoyang District, Changchun , Jilin 130021 , China.
  • 7 Manufacturing, Commonwealth Scientific and Industrial Research Organization (CSIRO) , Clayton , Vic 3168 , Australia.
  • 8 School of Biological Sciences & Maurice Wilkins Centre , University of Auckland , Auckland 1010 , New Zealand.
  • 9 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences , Guangzhou 510530 , China.
PMID: 30964293 DOI: 10.1021/acs.jmedchem.9b00327
Abstract

We report the design, optimization, and biological evaluation of nuclear receptor RORγ inverse agonists as therapeutic agents for prostate Cancer treatment. The most potent compound 27 (designated as XY101) exhibited cellular activity with an IC50 value of 30 nM in a cell-based reporter gene assay with good selectivity against Other nuclear receptor subtypes. The cocrystal structure of 27 in complex with the RORγ ligand binding domain provided a solid structural basis for its antagonistic mechanism. 27 potently inhibited cell growth, colony formation, and the expression of AR, AR-V7, and PSA. 27 also exhibited good metabolic stability and a pharmacokinetic profile with oral bioavailability of 59% and a half-life of 7.3 h. Notably, 27 demonstrated promising therapeutic effects with significant tumor growth inhibition in a prostate Cancer xenograft model in mice. The potent, selective, metabolically stable, and orally available RORγ inverse agonists represent a new class of compounds as potential therapeutics against prostate Cancer.

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