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J Med Chem. 2014 Nov 13;57(21):9019-27. doi: 10.1021/jm501120z. Epub 2014 Oct 31.

Biased multicomponent reactions to develop novel bromodomain inhibitors.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute , 450 Brookline Avenue, Boston, Massachusetts 02215, United States.

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.

PMID:
25314271
PMCID:
PMC4234447
DOI:
10.1021/jm501120z
[Indexed for MEDLINE]
Free PMC Article

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