2. Academic Validation
  3. Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC

Design, synthesis and biological evaluation of N-phenylquinazolin-4-amine hybrids as dual inhibitors of VEGFR-2 and HDAC

  • Eur J Med Chem. 2016 Feb 15:109:1-12. doi: 10.1016/j.ejmech.2015.12.033.
Fan-Wei Peng 1,  Ji Xuan 2,  Ting-Ting Wu 1,  Jia-Yu Xue 3,  Zi-Wei Ren 1,  Da-Ke Liu 1,  Xiu-Qi Wang 1,  Xin-Hang Chen 1,  Jia-Wei Zhang 1,  Yun-Gen Xu 4,  Lei Shi 5
Affiliations

Affiliations

  • 1 Jiangsu Key Laboratory of Drug Design and Optimization, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, 210009, PR China.
  • 2 81 Hospital of PLA, Nanjing, 210002, 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.
  • 5 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.
PMID: 26741358 DOI: 10.1016/j.ejmech.2015.12.033
Abstract

A single agent that simultaneously inhibits multiple targets may offer greater therapeutic benefits in Cancer than single-acting agents through interference with multiple pathways and potential synergistic action. In this work, a series of hybrids bearing N-phenylquinazolin-4-amine and hydroxamic acid moieties were designed and identified as dual VEGFR-2/HDAC inhibitors. Compound 6fd exhibited the most potent inhibitory activity against HDAC with IC50 of 2.2 nM and strong inhibitory effect against VEGFR-2 with IC50 of 74 nM. It also showed the most potent inhibitory activity against a human breast Cancer cell line MCF-7 with IC50 of 0.85 μM. Docking simulation supported the initial pharmacophoric hypothesis and suggested a common mode of interaction at the active binding sites of VEGFR-2 and HDLP ((Histone Deacetylase-Like Protein), which demonstrates that compound 6fd is a potential agent for Cancer therapy deserving further researching.

Keywords

Dual inhibitor; HDAC; N-Phenylquinazolin-4-amine hybrid; VEGFR-2.

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