Optimization of 3,5-Dimethylisoxazole Derivatives as Potent Bromodomain Ligands
作者： David S. Hewings , Oleg Fedorov , Panagis Filippakopoulos , Sarah Martin , Sarah Picaud
DOI: 10.1021/JM301588R
关键词:
摘要: The bromodomain protein module, which binds to acetylated lysine, is emerging as an important epigenetic therapeutic target. We report the structure-guided optimization of 3,5-dimethylisoxazole derivatives develop potent inhibitors BET (bromodomain and extra terminal domain) family with good ligand efficiency. X-ray crystal structures most compounds reveal key interactions required for high affinity at BRD4(1). Cellular studies demonstrate that phenol acetate lead showed strong antiproliferative effects on MV4;11 acute myeloid leukemia cells, shown other genetic BRD4 knockdown, whereas reported no general cytotoxicity in cancer cell lines tested.
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