Synthesis of selective PAK4 inhibitors for lung metastasis of lung cancer and melanoma cells
Acta Pharmaceutica Sinica B
;
(6): 2905-2922, 2022.
Article
in English
| WPRIM
| ID: wpr-939925
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).
Full text:
Available
Index:
WPRIM (Western Pacific)
Language:
English
Journal:
Acta Pharmaceutica Sinica B
Year:
2022
Type:
Article
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