Discovery of vanoxerine dihydrochloride as a CDK2/4/6 triple-inhibitor for the treatment of human hepatocellular carcinoma

Ying Zhu,Jian-Ge Qiu,Zhong-Kun Xia,Man‐Hon Wong ,Kwong‐Sak Leung ,Bing‐Hua Jiang ,Xi‐Nan Shi ,Kunbin Ke ,Jianying Zhang ,Gang Lü ,Shi‐Guo Wu ,Hongjian Li ,Rong Su,Chao Dong,Hui Zhao,Lin Wang,Rong Chen,Feng-Mei Zhou,Peng Gu,Marie Chia‐Mi Lin

doi:10.1186/s10020-021-00269-4

Abstract

BackgroundCyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC).MethodsWe used the combination of computational and experimental approaches to discover a CDK2/4/6 triple-inhibitor from FDA approved small-molecule drugs for the treatment of HCC.ResultsWe identified vanoxerine dihydrochloride as a new CDK2/4/6 inhibitor, and a strong cytotoxicdrugin human HCC QGY7703 and Huh7 cells (IC50: 3.79 μM for QGY7703and 4.04 μM for Huh7 cells). In QGY7703 and Huh7 cells, vanoxerine dihydrochloride treatment caused G1-arrest, induced apoptosis, and reduced the expressions of CDK2/4/6, cyclin D/E, retinoblastoma protein (Rb), as well as the phosphorylation of CDK2/4/6 and Rb. Drug combination study indicated that vanoxerine dihydrochloride and 5-Fu produced synergistic cytotoxicity in vitro in Huh7 cells. Finally, in vivo study in BALB/C nude mice subcutaneously xenografted with Huh7 cells, vanoxerine dihydrochloride (40 mg/kg, i.p.) injection for 21 days produced significant anti-tumor activity (p < 0.05), which was comparable to that achieved by 5-Fu (10 mg/kg, i.p.), with the combination treatment resulted in synergistic effect. Immunohistochemistry staining of the tumor tissues also revealed significantly reduced expressions of Rb and CDK2/4/6in vanoxerinedihydrochloride treatment group.ConclusionsThe present study isthe first report identifying a new CDK2/4/6 triple inhibitor vanoxerine dihydrochloride, and demonstrated that this drug represents a novel therapeutic strategy for HCC treatment.

Highlights

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second (Mazzanti et al 2016) cause of cancer-related death world-wide
We extended these strategies to screen for CDK2/4/6 triple inhibitors from Food and Drug Administration (FDA) approved drugs, and discovered vanoxerine dihydrochloride as a new CDK2/4/6 triple inhibitor for the treatment of hepatocellular carcinoma (HCC)
Computer‐aided structure‐based virtual screening for CDK2/4/6 triple inhibitors The chemical structures of a total of 3167 US Food and Drug Administration (FDA) approved drugs were gathered from the ZINC database (Irwin and Shoichet 2005; Irwin et al 2012)

Summary

Introduction

Hepatocellular carcinoma (HCC), the most common type of liver cancer, is the second (Mazzanti et al 2016) cause of cancer-related death world-wide. Surgical resection is the first line treatment, followed by liver transplantation and percutaneous ablation. There is a high frequency of tumor recurrence after surgical resection, and most HCCs are resistant to conventional chemotherapy and radiotherapy (Llovet et al 2015). (Jindal et al 2019), with sorafenib, a multitarget tyrosine kinase inhibitor (TKI) approved by FDA for the treatment of unrespectable HCC. Rapid development of drug resistance limited the uses. There is urgent need for the development of more effective drugs targeting different mechanisms. Cyclin-dependent kinases 2/4/6 (CDK2/4/6) play critical roles in cell cycle progression, and their deregulations are hallmarks of hepatocellular carcinoma (HCC)

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Conclusion