Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells.

Abstract

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).

• Authors: 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
• Journal: Acta pharmaceutica Sinica. B (Acta Pharm Sin B) Vol. 12 Issue 6 Pg. 2905-2922 (Jun 2022) ISSN: 2211-3835 [Print] Netherlands
• PMID: 35755272 (Publication Type: Journal Article)
• Copyright: © 2022 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.