Identification of a novel PAK1 inhibitor to treat pancreatic cancer

被引：0

作者：

Jiaqi Wang ^{[1
,2
,3
]}

Yonghua Zhu ^{[4
]}

Jiao Chen ^{[1
,2
,3
]}

Yuhan Yang ^{[5
]}

Lingxia Zhu ^{[1
,2
,3
]}

Jiayu Zhao ^{[1
,2
,3
]}

Yang Yang ^{[1
,2
,3
]}

Xueting Cai ^{[1
,2
,3
]}

Chunping Hu ^{[1
,2
,3
]}

Rafael Rosell ^{[6
]}

Xiaoyan Sun ^{[1
,2
,3
]}

Peng Cao ^{[1
,2
,3
,7
]}

机构：

[1] Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine

[2] Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine

[3] Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine

[4] Fullshare Health College, Nanjing University of Chinese Medicine

[5] Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine

[6] Cancer Biology and Precision Medicine Program, Germans Trias i Pujol University Hospital, Badalona

[7] Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, School of Public Health, Nanjing Medical University

来源：

Acta Pharmaceutica Sinica B | 2020年 / 10卷 / 04期

关键词：

PAK1; Pancreatic cancer; Inhibitor; Structure-based virtual screening; Synergistic effect;

D O I：

暂无

中图分类号：

R979.1 [抗肿瘤、抗癌药物];

学科分类号：

1007 ;

摘要：

Pancreatic cancer is one of the most aggressive cancers with poor prognosis and a low 5-year survival rate. The family of P21-activated kinases(PAKs) appears to modulate many signaling pathways that contribute to pancreatic carcinogenesis. In this work, we demonstrated that PAK1 is a critical regulator in pancreatic cancer cell growth. PAK1-targeted inhibition is therefore a new potential therapeutic strategy for pancreatic cancer. Our small molecule screening identified a relatively specific PAK1-targeted inhibitor, CP734. Pharmacological and biochemical studies indicated that CP734 targets residue V342 of PAK1 to inhibit its ATPase activity. Further in vitro and in vivo studies elucidated that CP734 suppresses pancreatic tumor growth through depleting PAK1 kinase activity and its downstream signaling pathways. Little toxicity of CP734 was observed in murine models. Combined with gemcitabine or 5-fluorouracil, CP734 also showed synergistic effects on the anti-proliferation of pancreatic cancer cells.All these favorable results indicated that CP734 is a new potential therapeutic candidate for pancreatic cancer.

引用

页码：603 / 614

页数：12

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