Research Papers:

Mass spectral analysis of the multikinase inhibitor BZG and its metabolites and analysis of their binding to vascular endothelial growth factor receptor-2

Yan Lou, Wenqi Qiu, Zhe Wu, Qian Wang, Yunqing Qiu _ and Su Zeng

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Oncotarget. 2017; 8:29951-29962. https://doi.org/10.18632/oncotarget.16264

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Yan Lou1, Wenqi Qiu1, Zhe Wu1, Qian Wang1, Yunqing Qiu1, Su Zeng2

1State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, The First Affiliated Hospital, Zhejiang University, Hangzhou, PR China

2Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, PR China

Correspondence to:

Yunqing Qiu, email: [email protected]

Keywords: hepatocellular carcinoma, novel multikinase inhibitor, metabolite, VEGFR-2, eHiTS

Received: January 25, 2017     Accepted: March 08, 2017     Published: March 16, 2017


We previously showed that BZG is a novel multitarget kinase inhibitor, which inhibited hepatocellular carcinoma in vivo and in vitro. In the present study, we used ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF MS) to characterize BZG and its metabolites generated in vivo. The probable metabolic mechanism was further confirmed by analysis of Phase I and Phase II metabolism in liver microsomes and with recombinant enzymes. In addition, the binding affinities of BZG metabolites to vascular endothelial growth factor receptor 2 (VEGFR2) were predicted using electronic high throughput screening (eHiTS). The results showed that BZG underwent phase I and phase II metabolism. We detected 11 BZG metabolites and identified hydroxylation, glucuronation, acetylation, sulfonation and degradation as the major metabolic processes in vivo and in vitro. Five of the eleven metabolites showed highly favorable eHiTS energy scores that were lower than sorafenib. Knowledge of the in vivo metabolic pathways of BZG and its binding affinities to VEGFR2 will be beneficial for further clinical development of BZG.

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