Structure-guided development of covalent TAK1 inhibitors.

Bioorganic & medicinal chemistry 2017 Feb 01

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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. Copyright © 2016 Elsevier Ltd. All rights reserved.

Citation

Li Tan, Deepak Gurbani, Ellen L Weisberg, John C Hunter, Lianbo Li, Douglas S Jones, Scott B Ficarro, Samar Mowafy, Chun-Pong Tam, Suman Rao, Guangyan Du, James D Griffin, Peter K Sorger, Jarrod A Marto, Kenneth D Westover, Nathanael S Gray. Structure-guided development of covalent TAK1 inhibitors. Bioorganic & medicinal chemistry. 2017 Feb 01;25(3):838-846