7xqe
Crystal Structure of human RORgamma (C455E) LBD in complex with compound XY039Crystal Structure of human RORgamma (C455E) LBD in complex with compound XY039
Structural highlights
Publication Abstract from PubMedThe retinoic acid receptor-related orphan receptor gamma (RORgamma) is regarded as an attractive therapeutic target for the treatment of prostate cancer. Herein, we report the identification, optimization, and evaluation of 1,2,3,4-tetrahydroquinoline derivatives as novel RORgamma inverse agonists, starting from high throughput screening using a thermal stability shift assay (TSA). The representative compounds 13e (designated as XY039) and 14a (designated as XY077) effectively inhibited the RORgamma transcriptional activity and exhibited excellent selectivity against other nuclear receptor subtypes. The structural basis for their inhibitory potency was elucidated through the crystallographic study of RORgamma LBD complex with 13e. Both 13e and 14a demonstrated reasonable antiproliferative activity, potently inhibited colony formation and the expression of AR, AR regulated genes, and other oncogene in AR positive prostate cancer cell lines. Moreover, 13e and 14a effectively suppressed tumor growth in a 22Rv1 xenograft tumor model in mice. This work provides new and valuable lead compounds for further development of drugs against prostate cancer. Discovery and pharmacological characterization of 1,2,3,4-tetrahydroquinoline derivatives as RORgamma inverse agonists against prostate cancer.,Wu XS, Luo XY, Li CC, Zhao XF, Zhang C, Chen XS, Lu ZF, Wu T, Yu HN, Peng C, Hu QQ, Shen H, Xu Y, Zhang Y Acta Pharmacol Sin. 2024 May 2. doi: 10.1038/s41401-024-01274-z. PMID:38698214[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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