Biased Multicomponent Reactions to Develop Novel Bromodomain Inhibitors

• Published in: Journal of medicinal chemistry 2014-11, Vol.57 (21), p.9019-9027
• Main Authors: McKeown, Michael R, Shaw, Daniel L, Fu, Harry, Liu, Shuai, Xu, Xiang, Marineau, Jason J, Huang, Yibo, Zhang, Xiaofeng, Buckley, Dennis L, Kadam, Asha, Zhang, Zijuan, Blacklow, Stephen C, Qi, Jun, Zhang, Wei, Bradner, James E
• Format: Article
• Language: English
• Subjects: Alkanesulfonic Acids - chemistry; Azepines - pharmacology; Cell Line, Tumor; Crystallography, X-Ray; Fluorocarbons - chemistry; Gene Expression Regulation; Humans; Imidazoles - chemical synthesis; Imidazoles - pharmacology; Inhibitory Concentration 50; Isoxazoles - chemistry; Ligands; Models, Molecular; Nuclear Proteins - antagonists & inhibitors; Nuclear Proteins - chemistry; Pyrazines - chemical synthesis; Pyrazines - pharmacology; Pyridines - chemical synthesis; Small Molecule Libraries - chemical synthesis; Structure-Activity Relationship; Transcription Factors - antagonists & inhibitors; Transcription Factors - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm501120z

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 K d 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.