From the Metabolic Signalling Laboratory and.
Protein Chemistry and Metabolism Unit, St. Vincent's Institute of Medical Research, University of Melbourne, Fitzroy 3065, Victoria, Australia.
J Biol Chem. 2018 Jun 8;293(23):8874-8885. doi: 10.1074/jbc.RA118.003547. Epub 2018 Apr 25.
Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor. SBI-0206965 inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C and inhibits cellular AMPK signaling. Biochemical characterization reveals that SBI-0206965 is a mixed-type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows that the drug occupies a pocket that partially overlaps the ATP active site in a type IIb inhibitor manner. SBI-0206965 has utility as a tool compound for investigating physiological roles for AMPK and provides fresh impetus to small-molecule AMPK inhibitor therapeutic development.
抑制代谢调节剂 AMP 激活的蛋白激酶 (AMPK) 因其在 AMPK 过度活跃导致预后不良的疾病中的治疗潜力而受到越来越多的研究，如已确立的癌症和神经退行性疾病。然而，AMPK 抑制性工具化合物在很大程度上仅限于化合物 C，其选择性较差。在这里，我们确定嘧啶衍生物 SBI-0206965 是一种直接的 AMPK 抑制剂。SBI-0206965 对 AMPK 的抑制作用比化合物 C 强 40 倍，激酶混杂性明显降低，并抑制细胞内 AMPK 信号转导。生化特性表明 SBI-0206965 是一种混合抑制剂。AMPK 激酶结构域/SBI-0206965 复合物的共晶结构表明，该药物占据了一个口袋，该口袋以 IIb 型抑制剂的方式部分重叠 ATP 活性位点。SBI-0206965 可用作研究 AMPK 生理作用的工具化合物，并为小分子 AMPK 抑制剂治疗的发展提供了新的动力。
