Identification of a novel PAK1 inhibitor to treat pancreatic cancer
Por:
Wang, JQ, Zhu, YH, Chen, J, Yang, YH, Zhu, LX, Zhao, JY, Yang, Y, Cai, XT, Hu, CP, Rosell, R, Sun, XY and Cao, P
Publicada:
1 abr 2020
Ahead of Print:
16 dic 2019
Resumen:
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. (C) 2020 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
Filiaciones:
Wang, JQ:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Zhu, YH:
Nanjing Univ Chinese Med, Fullshare Hlth Coll, Nanjing 210023, Peoples R China
Chen, J:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Yang, YH:
Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Gen Surg, Sch Med, Shanghai 200080, Peoples R China
Zhu, LX:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Zhao, JY:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Yang, Y:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Gen Surg, Sch Med, Shanghai 200080, Peoples R China
Cai, XT:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Hu, CP:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
:
Germans Trias & Pujol Univ Hosp, Canc Biol & Precis Med Program, Badalona 08916, Spain
Sun, XY:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Cao, P:
Nanjing Univ Chinese Med, Affiliated Hosp Integrated Tradit Chinese & Weste, Nanjing 210028, Peoples R China
Nanjing Univ Chinese Med, Sch Pharm, Dept Pharmacol, Nanjing 210023, Peoples R China
Jiangsu Prov Acad Tradit Chinese Med, Lab Cellular & Mol Biol, Nanjing 210028, Peoples R China
Nanjing Med Univ, Jiangsu Collaborat Innovat Ctr Canc Personalized, Sch Publ Hlth, Jiangsu Key Lab Canc Biomarkers Prevent & Treatme, Nanjing 211166, Peoples R China
Green Published, gold
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