Biased multicomponent reactions to develop novel bromodomain inhibitors.

Publication Type:

Journal Article


J Med Chem, Volume 57, Issue 21, p.9019-27 (2014)


Alkanesulfonic Acids, Azepines, Cell Line, Tumor, Crystallography, X-Ray, Fluorocarbons, Gene Expression Regulation, Humans, Imidazoles, Inhibitory Concentration 50, Isoxazoles, Ligands, Models, Molecular, Nuclear Proteins, Pyrazines, Pyridines, Small Molecule Libraries, Structure-Activity Relationship, Transcription Factors


<p>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. </p>