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

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• 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 R. Magnuson ; Steve Bellon ; Andrea G. Cochran
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：June 9, 2016
• 年：2016
• 卷：59
• 期：11
• 页码：5391-5402
• 全文大小：695K
• 年卷期：0
• ISSN：1520-4804

文摘

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.