2. Academic Validation
  3. Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors

Design and discovery of new selective and potent VEGF receptor 2 tyrosine kinase inhibitors

  • Bioorg Med Chem. 2023 Aug 15:91:117404. doi: 10.1016/j.bmc.2023.117404.
Fei Hou 1,  Yuhong Yao 1,  Yujiao Wei 1,  Yubo Wang 1,  Yangzi Cao 1,  Xinqiang Liu 1,  Liting Zheng 1,  Qingqing Zhang 1,  Yue Jiao 1,  Yukun Chen 1,  Yue Meng 1,  Yue Sun 1,  Yanjie Wu 1,  Jiefu Wang 2,  Junfeng Wang 3,  Zhou Wu 4,  Kun Zhang 5,  Mingming Wei 6,  Guang Yang 7
Affiliations

Affiliations

  • 1 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
  • 2 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China. Electronic address: jwang05@tmu.edu.cn.
  • 3 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, PR China. Electronic address: jwang08@tmu.edu.cn.
  • 4 China Resources Biopharmaceutical Co., Ltd., Beijing 100100, PR China. Electronic address: wuzhou7@crbiopharm.com.
  • 5 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: zhangkun@nankai.edu.cn.
  • 6 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: 8223428@nankai.edu.cn.
  • 7 The State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences, College of Pharmacy, Nankai University, Tianjin 300071, PR China. Electronic address: guang.yang@nankai.edu.cn.
PMID: 37429211 DOI: 10.1016/j.bmc.2023.117404
Abstract

A series of novel substituted 4-anilinoquinazolines and their related compounds were designed and prepared by 3D modeling as potential inhibitors of VEGFR-2. Evaluation of VEGFR inhibitory activities suggested that compound I10 was a more potent (IC50 = 0.11 nM) VEGFR-2 inhibitor than most of the listed drugs. Kinase panel assays demonstrated that compound I10 was the selective VEGFR-2 inhibitor. The prediction of 3D modeling unveiled a unique binding mode of this lead compound to VEGFR-2. Compound I10 exhibited remarkable anti-angiogenesis and anti-proliferation in HUVEC at low nanomolar concentrations. PK studies indicated that the lead compound possessed adequate oral bioavailability in various species. In vivo subcutaneous tumor model demonstrated that oral administration of I10 demonstrated potent efficacy in inhibiting tumor growth and angiogenesis. All these results suggested compound I10 is a potential drug candidate for Cancer treatment.

Keywords

Anti-cancer; Drug candidate; Kinase inhibitor; VEGFR-2.

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