State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Rd., Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
Eur J Med Chem. 2020 Jun 1;195:112277. doi: 10.1016/j.ejmech.2020.112277. Epub 2020 Apr 5.
Inhibition of MAP3K kinase ASK1 has been an attractive strategy for the treatment of nonalcoholic steatohepatitis and multiple sclerosis, among others. Herein, we reported the discovery of 2-pyridinyl urea-containing compound 14l (YD57) as a potent, small-molecule inhibitor of ASK1. 14l was selective against MAP3K kinases ASK2 and TAK1 (>140-fold), while it also inhibited several cell cycle regulating kinases with IC values in a range of 90-400 nM (<20-fold selectivity). As a consequence, 14l had stronger apoptosis induction, more potent G1 cell cycle arrest activities, and lower IC value of cell growth inhibition than that of GS4997 in HepG2 cancer cell line. On the other hand, 14l did not inhibit ASK1 and p38 phosphorylation in intact cells. We reason that the multi-target effects of 14l likely neutralized the activities caused by inhibition of cellular ASK1. Future studies of these ASK1 inhibitors should pay close attention to their kinome selectivity profile.
抑制丝裂原活化蛋白激酶激酶 ASK1 一直是治疗非酒精性脂肪性肝炎和多发性硬化症等疾病的一种有吸引力的策略。在此，我们报道了含 2-吡啶基脲的化合物 14l (YD57) 的发现，它是一种有效的 ASK1 小分子抑制剂。14l 对 MAP3K 激酶 ASK2 和 TAK1 具有选择性 (>140 倍)，同时还抑制了几种细胞周期调节激酶，IC 值在 90-400 nM 范围内（<20 倍选择性）。因此，与 GS4997 相比，14l 在 HepG2 癌细胞系中具有更强的凋亡诱导作用、更有效的 G1 细胞周期阻滞活性和更低的细胞生长抑制 IC 值。另一方面，14l 不能抑制完整细胞中 ASK1 和 p38 的磷酸化。我们认为，14l 的多靶点作用可能中和了抑制细胞 ASK1 引起的活性。未来对这些 ASK1 抑制剂的研究应密切关注其激酶组选择性特征。
