Molecular Basis for the N-Terminal Bromodomain-and-Extra-Terminal-Family Selectivity of a Dual Kinase−Bromodomain Inhibitor
| Autor: | Huarui Cui, Siva Kumar Talluri, Jin-Yi Zhu, Angela S. Carlson, Daniel A. Harki, Neeraj K. Mishra, Alex M. Ayoub, Joseph J. Topczewski, William C. K. Pomerantz, Norbert Berndt, Ernst Schönbrunn, Anand Divakaran, John C. Widen |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
BRD4 Protein domain Lysine Cellular homeostasis 01 natural sciences p38 Mitogen-Activated Protein Kinases Article 03 medical and health sciences Protein Domains Transcription (biology) Drug Discovery Humans Epigenetics Protein Kinase Inhibitors 010405 organic chemistry Kinase Chemistry Imidazoles Water 0104 chemical sciences Cell biology Bromodomain 030104 developmental biology A549 Cells Molecular Medicine |
| Popis: | 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-trisubstitutedimidazole 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. |
| Databáze: | OpenAIRE |
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