Discovery of 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase1 (ASK1)
Discovery of 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase1 (ASK1)
复制标题
发现含有 2-吡啶基脲的化合物 YD57 作为凋亡信号调节激酶 1 (ASK1) 的有效抑制剂
DOI：
10.1016/j.ejmech.2020.112277
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yujun Zhao
中科院分区：
文献类型：
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作者：
Shiyan Zhang;Chaoying Huang;Xilin Lyu;Peipei Wang;Yi Zang;Zengtao Wang;Huan Wang;Jia Li;Yujun Zhao
抑制MAP 3 K激酶ASK 1已成为治疗非酒精性脂肪性肝炎和多发性硬化等的有吸引力的策略。本文中，我们报道了发现含2-吡啶基脲的化合物141（YD 57）作为有效的ASK 1的小分子抑制剂。141对MAP 3 K激酶ASK 2和TAK 1具有选择性（>140倍），同时它还抑制几种细胞周期调节激酶，IC 50值在90-400 nM范围内（<20倍选择性）。结果表明，141对HepG 2细胞具有较强的诱导凋亡作用，较GS4997具有更强的G1期细胞阻滞活性，较GS4997具有更低的细胞生长抑制IC 50值。另一方面，14 l并不抑制完整细胞中的ASK 1和p38磷酸化。我们推断，14的多靶点效应可能中和了由细胞ASK 1抑制引起的活性。这些ASK 1抑制剂的未来研究应密切关注其激酶组选择性特征。
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 compound14l(YD57) as a potent, small-molecule inhibitor of ASK1.14lwas selective against MAP3K kinases ASK2 and TAK1 (>140-fold), while it also inhibited several cell cycle regulating kinases with IC50values in a range of 90–400 nM (<20-fold selectivity). As a consequence,14lhad stronger apoptosis induction, more potent G1 cell cycle arrest activities, and lower IC50value of cell growth inhibition than that of GS4997 in HepG2 cancer cell line. On the other hand,14ldid not inhibit ASK1 and p38 phosphorylation in intact cells. We reason that the multi-target effects of14llikely neutralized the activities caused by inhibition of cellular ASK1. Future studies of these ASK1 inhibitors should pay close attention to their kinome selectivity profile.