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 Pomerantz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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
Volume61
Issue number20
DOIs
StatePublished - Oct 25 2018

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Lysine
Phosphotransferases
Post Translational Protein Processing
Interleukin-8
Epigenomics
Histones
Homeostasis
Water
Neoplasms
Proteins
imidazole

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

Cite this

Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. / Divakaran, Anand; Talluri, Siva K.; Ayoub, Alex M.; Mishra, Neeraj K; Cui, Huarui; Widen, John C.; Berndt, Norbert; Zhu, Jin Yi; Carlson, Angela S; Topczewski, Joseph J; Schonbrunn, Ernst K.; Harki, Daniel A; Pomerantz, William C.

In: Journal of Medicinal Chemistry, Vol. 61, No. 20, 25.10.2018, p. 9316-9334.

Research output: Contribution to journalArticle

Divakaran, Anand ; Talluri, Siva K. ; Ayoub, Alex M. ; Mishra, Neeraj K ; Cui, Huarui ; Widen, John C. ; Berndt, Norbert ; Zhu, Jin Yi ; Carlson, Angela S ; Topczewski, Joseph J ; Schonbrunn, Ernst K. ; Harki, Daniel A ; Pomerantz, William C. / Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor. In: Journal of Medicinal Chemistry. 2018 ; Vol. 61, No. 20. pp. 9316-9334.
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