Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2

Lei Shi; Ting-Ting Wu; Zhi Wang; Jia-Yu Xue; Yun-Gen Xu

doi:10.1016/j.bmc.2014.07.008

Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2

Bioorg Med Chem. 2014 Sep 1;22(17):4735-44. doi: 10.1016/j.bmc.2014.07.008. Epub 2014 Jul 11.

Authors

Lei Shi¹, Ting-Ting Wu², Zhi Wang², Jia-Yu Xue³, Yun-Gen Xu⁴

Affiliations

¹ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: shilei@cpu.edu.cn.
² Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
³ Jiangsu Provincial Key Laboratory for Plant Ex Situ Conservation, Institute of Botany, Jiangsu Province and Chinese Academy of Sciences, Nanjing 210014, PR China.
⁴ Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: xyg@cpu.edu.cn.

PMID: 25082515
DOI: 10.1016/j.bmc.2014.07.008

Abstract

Both c-Met and VEGFR-2 are important targets for the treatment of cancers. In this study, a series of N-(2-phenyl-1H-benzo[d]imidazol-5-yl)quinazolin-4-amine derivatives were designed and identified as dual c-Met and VEGFR-2 inhibitors. Among these compounds bearing quinazoline and benzimidazole fragments, compound 7j exhibited the most potent inhibitory activity against c-Met and VEGFR-2 with IC50 of 0.05μM and 0.02μM, respectively. It also showed the highest anticancer activity against the tested cancer cell lines with IC50 of 1.5μM against MCF-7 and 8.7μM against Hep-G2. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, which demonstrates that compound 7j is a potential agent for cancer therapy deserving further researching.

Keywords: Benzimidazole; Dual inhibitor; Quinazoline; VEGFR-2; c-Met.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Benzimidazoles / chemical synthesis
Benzimidazoles / chemistry*
Benzimidazoles / pharmacology*
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
MCF-7 Cells
Molecular Docking Simulation
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Quinazolines / chemical synthesis
Quinazolines / chemistry
Quinazolines / pharmacology*
Structure-Activity Relationship
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Antineoplastic Agents
Benzimidazoles
N-(2-(4-fluorophenyl)-1H-benzo(d)imidazol-6-yl)quinazolin-4-amine
Protein Kinase Inhibitors
Quinazolines
benzimidazole
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2