7v2j
Crystal Structure of the first bromodomain of human BRD4 in complex with the inhibitor 33
Structural highlights
DiseaseBRD4_HUMAN Note=A chromosomal aberration involving BRD4 is found in a rare, aggressive, and lethal carcinoma arising in midline organs of young people. Translocation t(15;19)(q14;p13) with NUT which produces a BRD4-NUT fusion protein.[1] [2] FunctionBRD4_HUMAN Plays a role in a process governing chromosomal dynamics during mitosis (By similarity). Publication Abstract from PubMedBRD4 plays a key role in the regulation of gene transcription and has been identified as an attractive target for cancer treatment. In this study, we designed 26 new compounds by modifying 3-ethyl-benzo[d]isoxazole core with sulfonamides. Most compounds exhibited potent BRD4 binding activities with DeltaT(m) values exceeding 6 degrees C. Two crystal structures of 11h and 11r in complex with BRD4(1) were obtained to characterize the binding patterns. Compounds 11h and 11r were effective for BRD4(1) binding and showed remarkable anti-proliferative activity against MV4-11 cells with IC(50) values of 0.78 and 0.87 muM. Furthermore, 11r (0.5-10 muM) concentration-dependently inhibited the expression levels of oncogenes including c-Myc and CDK6 in MV4-11 cells. Moreover, 11r (0.5-10 muM) concentration-dependently blocked cell cycle in MV4-11 cells at G(0)/G(1) phase and induced cell apoptosis. Compound 11r may serve as a new lead compound for further drug development. Design, synthesis and pharmacological characterization of N-(3-ethylbenzo[d]isoxazol-5-yl) sulfonamide derivatives as BRD4 inhibitors against acute myeloid leukemia.,Zhang MF, Luo XY, Zhang C, Wang C, Wu XS, Xiang QP, Xu Y, Zhang Y Acta Pharmacol Sin. 2022 Oct;43(10):2735-2748. doi: 10.1038/s41401-022-00881-y. , Epub 2022 Mar 9. PMID:35264812[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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