Design and synthesis of 1H-indazole-3-carboxamide derivatives as potent and selective PAK1 inhibitors with anti-tumour migration and invasion activities

被引:5
作者
Zhang, Mingliang [1 ]
Fang, Xiaobao [1 ]
Wang, Cong [1 ]
Hua, Yi [1 ]
Huang, Chen [1 ]
Wang, Meng [1 ]
Zhu, Lu [1 ]
Wang, Zixu [1 ]
Gao, Yuhan [1 ]
Zhang, Tianyi [1 ]
Liu, Haichun [1 ]
Zhang, Yanmin [1 ]
Lu, Shuai [1 ]
Lu, Tao [1 ,2 ]
Chen, Yadong [1 ,2 ]
Li, Hongmei [1 ]
机构
[1] China Pharmaceut Univ, Lab Mol Design & Drug Discovery, Nanjing 211198, Peoples R China
[2] China Pharmaceut Univ, State Key Lab Nat Med, Nanjing 210009, Peoples R China
基金
中国国家自然科学基金; 中国博士后科学基金;
关键词
PAK1; inhibitor; Kinase selectivity; 1H-indazole-3-carboxamide scaffold; Anti-tumour metastasis; EPITHELIAL-MESENCHYMAL TRANSITION; P21-ACTIVATED KINASES; BIOLOGICAL EVALUATION; OPTIMIZATION; PALLADIUM; DISCOVERY; AMIDES;
D O I
10.1016/j.ejmech.2020.112517
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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 compound 301 exhibited 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 of 301 demonstrated 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. (C) 2020 Elsevier Masson SAS. All rights reserved.
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页数:18
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