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- W2083005728 abstract "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 Å resolution crystal structure. This research showcases new applications of fluorous and multicomponent chemical synthesis for the development of novel epigenetic inhibitors." @default.
- W2083005728 created "2016-06-24" @default.
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- W2083005728 date "2014-10-31" @default.
- W2083005728 modified "2023-10-01" @default.
- W2083005728 title "Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors" @default.
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- W2083005728 doi "https://doi.org/10.1021/jm501120z" @default.
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- W2083005728 hasPublicationYear "2014" @default.
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