Structure-guided development of covalent TAK1 inhibitors

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• 作者：Li Tan^a ; ^b ; ^j ; Deepak Gurbani^c ; ^d ; ^j ; Ellen L. Weisberg^e ; ^f ; John C. Hunter^c ; ^d ; Lianbo Li^c ; ^d ; Douglas S. Jones^g ; ^h ; Scott B. Ficarro^a ; ^b ; Samar Mowafy^a ; ^b ; ⁱ ; Chun-Pong Tam^a ; ^b ; Suman Rao^a ; ^b ; ^g ; Guangyan Du^a ; ^b ; James D. Griffin^e ; ^f ; Peter K. Sorger^g ; Jarrod A. Marto^a ; ^b ; Kenneth D. Westover^c ; ^d ; ^{Kenneth.Westover@UTSouthwestern.edu} ; Nathanael S. Gray^a ; ^b ; ^{Nathanael_Gray@dfci.harvard.edu}
• 关键词：Structure-based design ; TAK1 kinase inhibitors ; Covalent inhibitors ; 2 ; 4-Disubstituted pyrimidine ; Structure-activity relationship
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：25
• 期：3
• 页码：838-846
• 全文大小：3067 K
• 卷排序：25

文摘

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.