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
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
Department of Biochemistry, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA; Department of Radiation Oncology, The University of Texas, Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
Bioorg Med Chem. 2017 Feb 1;25(3):838-846. doi: 10.1016/j.bmc.2016.11.035. Epub 2016 Dec 9.
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.
TAK1（转化生长因子-β激活激酶1）是细胞因子和生长因子信号传导中必不可少的细胞内介质，也是治疗免疫疾病和癌症的潜在治疗靶点。在此，我们报告了一系列靶向Cys174的2,4-二取代嘧啶共价TAK1抑制剂的开发，Cys174是激酶激活环“DFG基序”紧邻的一个残基。TAK1与候选化合物的共晶体结构实现了基于结构的设计和生物学测试的迭代循环，从而得到优化的化合物。先导化合物如2和10对TAK1的生化选择性比对具有等效位置半胱氨酸残基的密切相关激酶MEK1和ERK1高10倍以上。相对于先前报道的大环天然产物TAK1抑制剂如5Z-7-氧代zeanol，这些化合物更小，更易于合成，并且表现出不同的激酶选择性谱。
