1.Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells.
Peilu SONG ; Fan ZHAO ; Dahong LI ; Jiqiang QU ; Miao YAO ; Yuan SU ; Hanxun WANG ; Miaomiao ZHOU ; Yujie WANG ; Yinli GAO ; Feng LI ; Dongmei ZHAO ; Fengjiao ZHANG ; Yu RAO ; Mingyu XIA ; Haitao LI ; Jian WANG ; Maosheng CHENG
Acta Pharmaceutica Sinica B 2022;12(6):2905-2922
The p21 activated kinase 4 (PAK4) is serine/threonine protein kinase that is critical for cancer progression. Guided by X-ray crystallography and structure-based optimization, we report a novel subseries of C-3-substituted 6-ethynyl-1H-indole derivatives that display high potential and specificity towards group II PAKs. Among these inhibitors, compound 55 exhibited excellent inhibitory activity and kinase selectivity, displayed superior anti-migratory and anti-invasive properties against the lung cancer cell line A549 and the melanoma cell line B16. Compound 55 exhibited potent in vivo antitumor metastatic efficacy, with over 80% and 90% inhibition of lung metastasis in A549 or B16-BL6 lung metastasis models, respectively. Further mechanistic studies demonstrated that compound 55 mitigated TGF-β1-induced epithelial-mesenchymal transition (EMT).
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