6mh1

Publication Abstract from PubMed

As regulators of transcription, epigenetic proteins that interpret post-translational modifications to N-terminal histone tails are essential for maintaining cellular homeostasis. When dysregulated, "reader" proteins become drivers of disease. In the case of bromodomains, which recognize N-epsilon-acetylated lysine, selective inhibition of individual bromodomain-and-extra-terminal (BET)-family bromodomains has proven challenging. We describe the >55-fold N-terminal-BET bromodomain selectivity of 1,4,5-trisubstituted-imidazole dual kinase-bromodomain inhibitors. Selectivity for the BRD4 N-terminal bromodomain (BRD4(1)) over its second bromodomain (BRD4(2)) arises from the displacement of ordered waters and the conformational flexibility of lysine-141 in BRD4(1). Cellular efficacy was demonstrated via reduction of c-Myc expression, inhibition of NF-kappaB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38alpha. These dual inhibitors provide a new scaffold for domain-selective inhibition of BRD4, the aberrant function of which plays a key role in cancer and inflammatory signaling.

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor.,Divakaran A, Talluri SK, Ayoub AM, Mishra NK, Cui H, Widen JC, Berndt N, Zhu JY, Carlson AS, Topczewski JJ, Schonbrunn EK, Harki DA, Pomerantz WCK J Med Chem. 2018 Oct 25;61(20):9316-9334. doi: 10.1021/acs.jmedchem.8b01248. Epub, 2018 Oct 16. PMID:30253095^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.