Diving into the Water: Inducible Binding Conformations for BRD4, TAF1(2), BRD9, and CECR2 Bromodomains

作者：Terry D. Crawford, Vickie Tsui, E. Megan Flynn, Shumei Wang, Alexander M. Taylor, Alexandre Côté, James E. Audia, Maureen H. Beresini, Daniel J. Burdick, Richard Cummings, Les A. Dakin, Martin Duplessis, Andrew C. Good, Michael C. Hewitt, Hon-Ren Huang, Hariharan Jayaram, James R. Kiefer, Ying Jiang, Jeremy Murray, Christopher G. Nasveschuk, Eneida Pardo, Florence Poy, F. Anthony Romero, Yong Tang, Jian Wang, Zhaowu Xu, Laura E. Zawadzke, Xiaoyu Zhu, Brian K. Albrecht, Steven Magnuson, S.F. Bellon, Andrea G. Cochran · 发表于：Journal of Medicinal Chemistry · 年份：2016 · DOI：10.1021/acs.jmedchem.6b00264 · 被引用次数：119 · 研究领域：Protein Degradation and Inhibitors、Multiple Myeloma Research and Treatments、Peptidase Inhibition and Analysis

The biological role played by non-BET bromodomains remains poorly understood, and it is therefore imperative to identify potent and highly selective inhibitors to effectively explore the biology of individual bromodomain proteins. A ligand-efficient nonselective bromodomain inhibitor was identified from a 6-methyl pyrrolopyridone fragment. Small hydrophobic substituents replacing the N-methyl group were designed directing toward the conserved bromodomain water pocket, and two distinct binding conformations were then observed. The substituents either directly displaced and rearranged the conserved solvent network, as in BRD4(1) and TAF1(2), or induced a narrow hydrophobic channel adjacent to the lipophilic shelf, as in BRD9 and CECR2. The preference of distinct substituents for individual bromodomains provided selectivity handles useful for future lead optimization efforts for selective BRD9, CECR2, and TAF1(2) inhibitors.