Acta Pharmaceutica Sinica B (Jun 2022)
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
Affiliations
- Peilu Song
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical Biology, Tsinghua University, Beijing 100084, China
- Fan Zhao
- MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China
- Dahong Li
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, Shenyang 110016, China
- Jiqiang Qu
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shengyang 110016, China
- Miao Yao
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
- Yuan Su
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Hanxun Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Miaomiao Zhou
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
- Yujie Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Yinli Gao
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Feng Li
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang 110001, China
- Dongmei Zhao
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China
- Fengjiao Zhang
- Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China
- Yu Rao
- MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry Chemical Biology, Tsinghua University, Beijing 100084, China
- Mingyu Xia
- School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shengyang 110016, China; Corresponding authors. Tel.: +86 24 43520012 (Maosheng Cheng); Tel.: +86 24 42522398 (Mingyu Xia); Tel.: + 86 10 62771392 (Haitao Li); Tel.: +86 24 43520227 (Jian Wang).
- Haitao Li
- MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China; Corresponding authors. Tel.: +86 24 43520012 (Maosheng Cheng); Tel.: +86 24 42522398 (Mingyu Xia); Tel.: + 86 10 62771392 (Haitao Li); Tel.: +86 24 43520227 (Jian Wang).
- Jian Wang
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding authors. Tel.: +86 24 43520012 (Maosheng Cheng); Tel.: +86 24 42522398 (Mingyu Xia); Tel.: + 86 10 62771392 (Haitao Li); Tel.: +86 24 43520227 (Jian Wang).
- Maosheng Cheng
- Key Laboratory of Structure-Based Drug Design & Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China; Corresponding authors. Tel.: +86 24 43520012 (Maosheng Cheng); Tel.: +86 24 42522398 (Mingyu Xia); Tel.: + 86 10 62771392 (Haitao Li); Tel.: +86 24 43520227 (Jian Wang).
- Journal volume & issue
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Vol. 12,
no. 6
pp. 2905 – 2922
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).
