8z69

Crystal Structure of the second bromodomain of human BRD2 BD2 in complex with the inhibitor Y13195

spinqualitylabelsall models 8z69, resolution 1.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8z69 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.77Å Ligands: A1L0Y, EDO, FMT, GOL, NA, PEG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BRD2_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. Publication Abstract from PubMed Pan-BD2 inhibitors have been shown to retain an antileukemia effect and display less dose-limiting toxicities than pan-BET inhibitors. However, it is necessary to consider the potential off-target toxicity associated with the inhibition of four BET BD2 proteins. To date, no BRD4 BD2 domain selective inhibitor has been reported. Based on our previous pan-BD2 inhibitor 12 (XY153), we successfully identified 16o (XY221) as the first BRD4 BD2-selective inhibitor. 16o demonstrated potent binding affinity for BRD4 BD2 (IC(50) = 5.8 nM), along with high pan-BD2 selectivity (667-fold over BRD4 BD1) and BRD4 BD2 domain selectivity (9-32-fold over BRD2/3/T BD2). The BRD4 BD2 selectivity of 16o was further confirmed by the BLI assay, showing 66-144-fold selectivity over other BET BD2 domains. 16o exhibited good liver microsomal stability (T(1/2) > 120 min) and pharmacokinetic properties (F = 13.1%). These data indicate that 16o may serve as a valuable candidate for BRD4 BD2 advancing epigenetic research. Discovery of the First BRD4 Second Bromodomain (BD2)-Selective Inhibitors.,Li J, Hu Q, Zhu R, Dong R, Shen H, Hu J, Zhang C, Zhang X, Xu T, Xiang Q, Zhang Y, Lin B, Zhao L, Wu X, Xu Y J Med Chem. 2024 Nov 27. doi: 10.1021/acs.jmedchem.4c02516. PMID:39602227 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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