7wna | pdb_00007wna
Crystal Structure of the second bromodomain of human BRD2 in complex with the inhibitor Y13120
Structural highlights
FunctionBRD2_HUMAN May play a role in spermatogenesis or folliculogenesis (By similarity). Binds hyperacetylated chromatin and plays a role in the regulation of transcription, probably by chromatin remodeling. Regulates transcription of the CCND1 gene. Plays a role in nucleosome assembly.[1] Publication Abstract from PubMedPan-bromodomain and extra terminal (Pan-BET) inhibitors show profound efficacy but exhibit pharmacology-driven toxicities in clinical trials. The development of domain-selective BET inhibitors to separate efficacy and toxicity is urgently needed. Herein, we report a series of furo[3,2-c]pyridin-4(5H)-one derivatives as novel BD2-selective BET inhibitors. The representative compound 8l (XY153) potently bound to BRD4 BD2 with an half-maximum inhibitory concentration (IC50) value of 0.79 nM and displayed 354-fold selectivity over BRD4 BD1. Besides, 8l exhibited 6-fold BRD4 BD2 domain selectivity over other BET BD2 domains. Compound 8l displayed potent antiproliferative activity against multiple tumor cell lines, especially MV4-11 (IC50 = 0.55 nM), while showing weak cytotoxicity against the normal lung fibroblast cell line. It highlights the safety profile of this series of BD2 inhibitors. 8l also demonstrated good metabolic stability in vitro. These data indicate that 8l may serve as a new and valuable lead compound for the development of potential therapeutics against acute myeloid leukemia (AML). Structure-Based Discovery and Optimization of Furo[3,2-c]pyridin-4(5H)-one Derivatives as Potent and Second Bromodomain (BD2)-Selective Bromo and Extra Terminal Domain (BET) Inhibitors.,Li J, Zhang C, Xu H, Wang C, Dong R, Shen H, Zhuang X, Chen X, Li Q, Lu J, Zhang M, Wu X, Loomes KM, Zhou Y, Zhang Y, Liu J, Xu Y J Med Chem. 2022 Apr 14;65(7):5760-5799. doi: 10.1021/acs.jmedchem.2c00100. Epub , 2022 Mar 25. PMID:35333526[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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