McKeown, Michael RShaw, Daniel LFu, HarryLiu, ShuaiXu, XiangMarineau, Jason JHuang, YiboZhang, XiaofengBuckley, Dennis LKadam, AshaZhang, ZijuanBlacklow, StephenQi, JunZhang, WeiBradner, James E2015-11-032014McKeown, M., D. L. Shaw, H. Fu, S. Liu, X. Xu, J. J. Marineau, Y. Huang, et al. 2014. “Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors.” Journal of Medicinal Chemistry 57 (21): 9019-9027. doi:10.1021/jm501120z. http://dx.doi.org/10.1021/jm501120z.0022-2623http://nrs.harvard.edu/urn-3:HUL.InstRepos:23474045BET 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 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors.en-USArticleJournal Article2015-11-0310.1021/jm501120z