Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor

Anand Divakaran, Siva K. Talluri, Alex M. Ayoub, Neeraj K. Mishra, Huarui Cui, John C. Widen, Norbert Berndt, Jin Yi Zhu, Angela S. Carlson, Joseph J. Topczewski, Ernst K. Schonbrunn, Daniel A. Harki, William C.K. Pomerantz

Research output: Contribution to journalArticlepeer-review

42 Scopus citations


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-ϵ-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-κB signaling, and suppression of IL-8 production through potential synergistic inhibition of BRD4(1) and p38α. 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.

Original languageEnglish (US)
Pages (from-to)9316-9334
Number of pages19
JournalJournal of medicinal chemistry
Issue number20
StatePublished - Oct 25 2018

Bibliographical note

Funding Information:
This work was supported by the NSF (Grant CHE-1352019, W.C.K.P.) AHA (Grant 15SDG25710427, W.C.K.P.), NIGMS (Grant R35GM124718), and the University of Minnesota Masonic Cancer Center (Pre-R01 pilot grant D.A.H. and W.C.K.P.). A.D. was supported by the NIH Chemistry-Biology Interface Training Grant at the University of Minnesota (5T32GM008700-18). Isothermal-titration calorimetry and nuclear-magnetic-resonance spectroscopy were carried out using instruments funded by NIH Shared Instrumentation Grants (S10-OD017982 and S10-OD011952, respectively). We also thank the Moffitt Chemical Biology Core for use of the protein crystallography facility (NCI Grant P30-CA076292). BI-BODIPY was a generous gift from Wei Zhang at the University of Massachusetts, Boston. We thank Prof. Brian Smith for providing the BRD4 Bromodomain construct BRD4 (1 + 2) spanning residues 38-460.

Publisher Copyright:
Copyright © 2018 American Chemical Society.


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