Structure-guided development of covalent TAK1 inhibitors

• Published in: Bioorganic & medicinal chemistry 2017-02, Vol.25 (3), p.838-846
• Main Authors: Tan, Li, Gurbani, Deepak, Weisberg, Ellen L., Hunter, John C., Li, Lianbo, Jones, Douglas S., Ficarro, Scott B., Mowafy, Samar, Tam, Chun-Pong, Rao, Suman, Du, Guangyan, Griffin, James D., Sorger, Peter K., Marto, Jarrod A., Westover, Kenneth D., Gray, Nathanael S.
• Format: Article
• Language: English
• Subjects: 2,4-Disubstituted pyrimidine; Animals; Covalent inhibitors; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; MAP Kinase Kinase Kinases - antagonists & inhibitors; MAP Kinase Kinase Kinases - metabolism; Mice; Microsomes, Liver - chemistry; Microsomes, Liver - metabolism; Models, Molecular; Molecular Structure; Protein Kinase Inhibitors - chemical synthesis; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - chemistry; Pyrimidines - pharmacology; Structure-Activity Relationship; Structure-based design; TAK1 kinase inhibitors
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2016.11.035

[Display omitted] TAK1 (transforming growth factor-β-activated kinase 1) is an essential intracellular mediator of cytokine and growth factor signaling and a potential therapeutic target for the treatment of immune diseases and cancer. Herein we report development of a series of 2,4-disubstituted pyrimidine covalent TAK1 inhibitors that target Cys174, a residue immediately adjacent to the ‘DFG-motif’ of the kinase activation loop. Co-crystal structures of TAK1 with candidate compounds enabled iterative rounds of structure-based design and biological testing to arrive at optimized compounds. Lead compounds such as 2 and 10 showed greater than 10-fold biochemical selectivity for TAK1 over the closely related kinases MEK1 and ERK1 which possess an equivalently positioned cysteine residue. These compounds are smaller, more easily synthesized, and exhibit a different spectrum of kinase selectivity relative to previously reported macrocyclic natural product TAK1 inhibitors such as 5Z-7-oxozeanol.