Identification of a novel PAK1 inhibitor to treat pancreatic cancer

Jiaqi Wang; Yonghua Zhu; Jiao Chen; Yuhan Yang; Lingxia Zhu; Jiayu Zhao; Yang Yang; Xueting Cai; Chunping Hu; Rafael Rosell; Xiaoyan Sun; Peng Cao

doi:10.1016/j.apsb.2019.11.015

Identification of a novel PAK1 inhibitor to treat pancreatic cancer

Acta Pharm Sin B. 2020 Apr;10(4):603-614. doi: 10.1016/j.apsb.2019.11.015. Epub 2019 Dec 16.

Authors

Jiaqi Wang^{1

2

3}, Yonghua Zhu⁴, Jiao Chen^{1

2

3}, Yuhan Yang⁵, 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 Rosell⁶, Xiaoyan Sun^{1

2

3}, Peng Cao^{1

2

3

7}

Affiliations

¹ Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, China.
² Department of Pharmacology, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
³ Laboratory of Cellular and Molecular Biology, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing 210028, China.
⁴ Fullshare Health College, Nanjing University of Chinese Medicine, Nanjing 210023, China.
⁵ Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
⁶ Cancer Biology and Precision Medicine Program, Germans Trias i Pujol University Hospital, Badalona, Badalona 08916, Spain.
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, Nanjing 211166, China.

Abstract

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.

Keywords: 5-FU, 5-fluorouracil; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ANOVA, analysis of variance; AST, aspartate aminotransferase; BCL-2, B-cell lymphoma-2; BUN, blood urea nitrogen; CCK-8, cell counting kit-8; CDC42, cell division cycle 42; DMEM, Dulbecco's modified Eagle's medium; DMSO, dimethylsulfoxide; ERK, extracellular regulated protein kinase; GEPIA, gene expression profiling interactive analysis; GTEx, genotype-tissue expression; Gem, gemcitabine; HEK293, human embryonic kidney 293; HTVS, high-throughput virtual screening; IMEM, improved minimum essential medium; IP, immunoprecipitation; Inhibitor; MEK, mitogen-activated protein kinase kinase; MEM, modified Eagle's medium; NSCLC, non-small cell lung cancer; OHP, oxaliplatin; OS, overall survival; PAK, P21-activated kinase; PAK1; PARP, poly(ADP-ribose) polymerase; PAX, paclitaxel; PSCs, pancreatic stellate cells; PUMA, P53 upregulated modulator of apoptosis; PVDF, polyvinylidene fluoride; Pancreatic cancer; RAC1, Rac family small GTPase 1; RIPA, radio immunoprecipitation assay; RPMI1640, Roswell Park Memorial Institute 1640 medium; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; SP, standard precision; Structure-based virtual screening; Synergistic effect; TCGA, The Cancer Genome Atlas; TUNEL, terminal deoxynucleotidyl transferase dUTP nick end labeling; XP, extra precision.