TY - JOUR
T1 - Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase-Bromodomain Inhibitor
AU - Divakaran, Anand
AU - Talluri, Siva K.
AU - Ayoub, Alex M.
AU - Mishra, Neeraj K.
AU - Cui, Huarui
AU - Widen, John C.
AU - Berndt, Norbert
AU - Zhu, Jin Yi
AU - Carlson, Angela S.
AU - Topczewski, Joseph J.
AU - Schonbrunn, Ernst K.
AU - Harki, Daniel A.
AU - Pomerantz, William C.K.
N1 - Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2018/10/25
Y1 - 2018/10/25
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.8b01248
DO - 10.1021/acs.jmedchem.8b01248
M3 - Article
C2 - 30253095
AN - SCOPUS:85055120156
SN - 0022-2623
VL - 61
SP - 9316
EP - 9334
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 20
ER -