Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities.
Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities.
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DOI：
10.1016/j.ejmech.2020.112517
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发表时间：
2020-07
影响因子：
6.7
通讯作者：
Mingliang Zhang;Xiaobao Fang;Cong Wang;Yi Hua;Chen Huang;M. Wang;Lu Zhu;Zixu Wang;Yuhan Gao;Tianyi Zhang;Haichun Liu;Yanmin Zhang;Shuai Lu;T. Lu;Yadong Chen;Hongmei Li
中科院分区：
文献类型：
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作者：
Mingliang Zhang;Xiaobao Fang;Cong Wang;Yi Hua;Chen Huang;M. Wang;Lu Zhu;Zixu Wang;Yuhan Gao;Tianyi Zhang;Haichun Liu;Yanmin Zhang;Shuai Lu;T. Lu;Yadong Chen;Hongmei Li
p21 激活激酶 1 (PAK1) 的异常激活与肿瘤进展相关，PAK1 已被认为是抗癌药物发现的有希望的靶点。然而，开发具有令人满意的激酶选择性和良好的理化性质的有效 PAK1 抑制剂仍然是一项艰巨的挑战。在此，我们使用基于片段的筛选方法将 1H-indmaze-3-carboxamide 衍生物鉴定为潜在的 PAK1 抑制剂。代表性化合物 30 对 29 种激酶具有出色的酶抑制作用 (PAK1 IC50 = 9.8 nM) 和高 PAK1 选择性。构效关系 (SAR) 分析表明，在深后袋中取代适当的疏水环并在本体溶剂区域中引入亲水基团对于 PAK1 抑制活性和选择性至关重要。此外，30 的 hERG 通道活性表明其 hERG 毒性风险较低。此外，它通过下调 Snail 表达，显着抑制 MDA-MB-231 细胞的迁移和侵袭，而不影响肿瘤生长。这些结果提供了一种针对PAK1的新型化学支架，并表明1H-吲唑-3-甲酰胺衍生物可以作为开发潜在的选择性PAK1抑制剂的先导化合物。
Aberrant activation of p21-activated kinase 1 (PAK1) is associated with tumour progression, and PAK1 has been recognized as a promising target for anticancer drug discovery. However, the development of potent PAK1 inhibitors with satisfactory kinase selectivity and favourable physicochemical properties remains a daunting challenge. Herein, we identified the 1H-indazole-3-carboxamide derivatives as potential PAK1 inhibitors using a fragment-based screening approach. The representative compound30lexhibited excellent enzyme inhibition (PAK1 IC50= 9.8 nM) and high PAK1 selectivity toward a panel of 29 kinases. The Structure-activity relationship (SAR) analysis showed that substituting of an appropriate hydrophobic ring in the deep back pocket and introducing a hydrophilic group in the bulk solvent region were critical for PAK1 inhibitory activity and selectivity. Additionally, the hERG channel activity of30ldemonstrated its low risk of hERG toxicity. Furthermore, it significantly suppressed the migration and invasion of MDA-MB-231 cells by downregulating Snail expression without affecting the tumour growth. These results provide a new type of chemical scaffolds targeting PAK1 and suggested that 1H-indazole-3-carboxamide derivatives may serve as lead compounds for the development of potential and selective PAK1 inhibitors.