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N-TERMINAL BROMODOMAIN OF HUMAN BRD4 with (5-(4-chloro-1-((tetrahydro-2H-pyran-4-yl)methyl)-1H-imidazol-2-yl)-1,3-dimethylpyridin-2(1H)-one
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 PubMedThe bromodomain and extra terminal (BET) family of bromodomain-containing proteins are important epigenetic regulators that elicit their effect through binding histone tail N-acetyl lysine (KAc) post-translational modifications. Recognition of such markers has been implicated in a range of oncology and immune diseases and, as such, small-molecule inhibition of the BET family bromodomain-KAc protein-protein interaction has received significant interest as a therapeutic strategy, with several potential medicines under clinical evaluation. This work describes the structure- and property-based optimization of a ligand and lipophilic efficient pan-BET bromodomain inhibitor series to deliver candidate I-BET787 (70) that demonstrates efficacy in a mouse model of inflammation and suitable properties for both oral and intravenous (IV) administration. This focused two-phase explore-exploit medicinal chemistry effort delivered the candidate molecule in 3 months with less than 100 final compounds synthesized. Structure- and Property-Based Optimization of Efficient Pan-Bromodomain and Extra Terminal Inhibitors to Identify Oral and Intravenous Candidate I-BET787.,Hirst DJ, Bamborough P, Al-Mahdi N, Angell DC, Barnett HA, Baxter A, Bit RA, Brown JA, Chung CW, Craggs PD, Davis RP, Demont EH, Ferrie A, Gordon LJ, Harada I, Ho TCT, Holyer ID, Hooper-Greenhill E, Jones KL, Lindon MJ, Lovatt C, Lugo D, Maller C, McGonagle G, Messenger C, Mitchell DJ, Pascoe DD, Patel VK, Patten C, Poole DL, Shah RR, Rioja I, Stafford KAJ, Tape D, Taylor S, Theodoulou NH, Tomlinson L, Wall ID, Wellaway CR, White G, Prinjha RK, Humphreys PG J Med Chem. 2024 Jun 27;67(12):10464-10489. doi: 10.1021/acs.jmedchem.4c00959. , Epub 2024 Jun 12. PMID:38866424[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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