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

Mingliang Zhang; Xiaobao Fang; Cong Wang; Yi Hua; Chen Huang; Meng Wang; Lu Zhu; Zixu Wang; Yuhan Gao; Tianyi Zhang; Haichun Liu; Yanmin Zhang; Shuai Lu; Tao Lu; Yadong Chen; Hongmei Li

doi:10.1016/j.ejmech.2020.112517

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

Eur J Med Chem. 2020 Oct 1:203:112517. doi: 10.1016/j.ejmech.2020.112517. Epub 2020 Jul 6.

Authors

Mingliang Zhang¹, Xiaobao Fang¹, Cong Wang¹, Yi Hua¹, Chen Huang¹, Meng Wang¹, Lu Zhu¹, Zixu Wang¹, Yuhan Gao¹, Tianyi Zhang¹, Haichun Liu¹, Yanmin Zhang¹, Shuai Lu¹, Tao Lu², Yadong Chen³, Hongmei Li⁴

Affiliations

¹ Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China.
² Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: lutao@cpu.edu.cn.
³ Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 210009, PR China. Electronic address: ydchen@cpu.edu.cn.
⁴ Laboratory of Molecular Design and Drug Discovery, China Pharmaceutical University, Nanjing, 211198, PR China. Electronic address: lihongmei@cpu.edu.cn.

PMID: 32846314
DOI: 10.1016/j.ejmech.2020.112517

Abstract

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 30l 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 30l 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.

Keywords: 1H-indazole-3-carboxamide scaffold; Anti-tumour metastasis; Kinase selectivity; PAK1 inhibitor.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Cell Movement / drug effects*
Chemistry Techniques, Synthetic
Drug Design*
Humans
Hydrophobic and Hydrophilic Interactions
Indazoles / chemical synthesis*
Indazoles / chemistry
Indazoles / pharmacology*
Inhibitory Concentration 50
Neoplasm Invasiveness
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology
p21-Activated Kinases / antagonists & inhibitors*

Substances

Antineoplastic Agents
Indazoles
Protein Kinase Inhibitors
p21-Activated Kinases