Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors
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- 作者：Michael R McKeown ; Daniel L Shaw ; Harry Fu ; Shuai Liu ; Xiang Xu ; Jason J Marineau ; Yibo Huang ; Xiaofeng Zhang ; Dennis L Buckley ; Asha Kadam ; Zijuan Zhang ; Stephen C Blacklow ; Jun Qi ; Wei Zhang ; James E Bradner
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：November 13, 2014
- 年：2014
- 卷：57
- 期：21
- 页码：9019-9027
- 全文大小：431K
- ISSN：1520-4804
文摘
BET bromodomain inhibition has contributed new insights into gene regulation and emerged as a promising therapeutic strategy in cancer. Structural analogy of early methyl-triazolo BET inhibitors has prompted a need for structurally dissimilar ligands as probes of bromodomain function. Using fluorous-tagged multicomponent reactions, we developed a focused chemical library of bromodomain inhibitors around a 3,5-dimethylisoxazole biasing element with micromolar biochemical IC50. Iterative synthesis and biochemical assessment allowed optimization of novel BET bromodomain inhibitors based on an imidazo[1,2-a]pyrazine scaffold. Lead compound 32 (UMB-32) binds BRD4 with a Kd of 550 nM and 724 nM cellular potency in BRD4-dependent lines. Additionally, compound 32 shows potency against TAF1, a bromodomain-containing transcription factor previously unapproached by discovery chemistry. Compound 32 was cocrystallized with BRD4, yielding a 1.56 脜 resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.