Identification of a novel PAK1 inhibitor to treat pancreatic cancer
| Autor: | Lingxia Zhu, Peng Cao, Yonghua Zhu, Jiao Chen, Rafael Rosell, Yuhan Yang, Chunping Hu, Xiaoyan Sun, Xueting Cai, Jiayu Zhao, Yang Yang, Jiaqi Wang |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
BCL-2
B-cell lymphoma-2 BUN blood urea nitrogen PARP poly(ADP-ribose) polymerase PSCs pancreatic stellate cells HEK293 human embryonic kidney 293 Regulator PAX paclitaxel AST aspartate aminotransferase OHP oxaliplatin 0302 clinical medicine PAK1 Pancreatic tumor Medicine General Pharmacology Toxicology and Pharmaceutics HTVS high-throughput virtual screening ANOVA analysis of variance XP extra precision RAC1 Rac family small GTPase 1 0303 health sciences DMEM Dulbecco's modified Eagle's medium Kinase SDS-PAGE sodium dodecyl sulfate-polyacrylamide gel electrophoresis IP immunoprecipitation Structure-based virtual screening PUMA P53 upregulated modulator of apoptosis GTEx genotype-tissue expression 030220 oncology & carcinogenesis Signal transduction medicine.drug SP standard precision Original article IMEM improved minimum essential medium Inhibitor DMSO dimethylsulfoxide PVDF polyvinylidene fluoride RIPA radio immunoprecipitation assay ERK extracellular regulated protein kinase TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling CDC42 cell division cycle 42 OS overall survival 03 medical and health sciences CCK-8 cell counting kit-8 Pancreatic cancer ALT alanine aminotransferase NSCLC non-small cell lung cancer PAK P21-activated kinase MEK mitogen-activated protein kinase kinase Survival rate GEPIA gene expression profiling interactive analysis 030304 developmental biology ALP alkaline phosphatase business.industry lcsh:RM1-950 MEM modified Eagle's medium medicine.disease Gemcitabine lcsh:Therapeutics. Pharmacology Cancer research Synergistic effect RPMI1640 Roswell Park Memorial Institute 1640 medium Gem gemcitabine TCGA The Cancer Genome Atlas 5-FU 5-fluorouracil business |
| Zdroj: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 10, Iss 4, Pp 603-614 (2020) |
| ISSN: | 2211-3835 |
| Popis: | 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. Graphical abstract CP734 was identified as a relatively selective inhibitor of PAK1 by structure-based virtual screening. It significantly suppressed pancreatic cancer cell growth both in vitro and in xenograft models. This study will provide molecular insights into the development of novel PAK1 kinase inhibitors, which may benefit anti-cancer drug candidate development.Image 1 |
| Databáze: | OpenAIRE |
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