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Discovery of a 2-pyridinyl urea-containing compound YD57 as a potent inhibitor of apoptosis signal-regulating kinase 1 (ASK1).
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-04-05 , DOI: 10.1016/j.ejmech.2020.112277 Shiyan Zhang 1 , Chaoying Huang 2 , Xilin Lyu 3 , Peipei Wang 3 , Yi Zang 3 , Zengtao Wang 3 , Huan Wang 3 , Jia Li 4 , Yujun Zhao 1
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2020-04-05 , DOI: 10.1016/j.ejmech.2020.112277 Shiyan Zhang 1 , Chaoying Huang 2 , Xilin Lyu 3 , Peipei Wang 3 , Yi Zang 3 , Zengtao Wang 3 , Huan Wang 3 , Jia Li 4 , Yujun Zhao 1
Affiliation
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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 IC50 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 IC50 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.
中文翻译：
发现了一种含有2-吡啶基脲的化合物YD57，它是凋亡信号调节激酶1（ASK1）的有效抑制剂。
抑制MAP3K激酶ASK1已成为治疗非酒精性脂肪性肝炎和多发性硬化症的诱人策略。在此，我们报道了发现含有2-吡啶基脲的化合物14l（YD57）作为有效的小分子ASK1抑制剂的发现。14l对MAP3K激酶ASK2和TAK1具有选择性（> 140倍），同时它也抑制了几种细胞周期调节激酶，IC50值在90-400 nM之间（选择性<20倍）。结果，与HepG2癌细胞系中的GS4997相比，14l具有更强的凋亡诱导，更强的G1细胞周期阻滞活性和更低的IC50值抑制细胞生长。另一方面，14l不能抑制完整细胞中的ASK1和p38磷酸化。我们认为14l的多靶点作用可能会中和由抑制细胞ASK1引起的活性。这些ASK1抑制剂的未来研究应密切关注其kinome选择性概况。
更新日期：2020-04-06
中文翻译：
发现了一种含有2-吡啶基脲的化合物YD57，它是凋亡信号调节激酶1（ASK1）的有效抑制剂。
抑制MAP3K激酶ASK1已成为治疗非酒精性脂肪性肝炎和多发性硬化症的诱人策略。在此，我们报道了发现含有2-吡啶基脲的化合物14l（YD57）作为有效的小分子ASK1抑制剂的发现。14l对MAP3K激酶ASK2和TAK1具有选择性（> 140倍），同时它也抑制了几种细胞周期调节激酶，IC50值在90-400 nM之间（选择性<20倍）。结果，与HepG2癌细胞系中的GS4997相比，14l具有更强的凋亡诱导，更强的G1细胞周期阻滞活性和更低的IC50值抑制细胞生长。另一方面，14l不能抑制完整细胞中的ASK1和p38磷酸化。我们认为14l的多靶点作用可能会中和由抑制细胞ASK1引起的活性。这些ASK1抑制剂的未来研究应密切关注其kinome选择性概况。
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