2. Academic Validation
  3. Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis

Novel dual inhibitors targeting CDK4 and VEGFR2 synergistically suppressed cancer progression and angiogenesis

  • Eur J Med Chem. 2019 Nov 1:181:111541. doi: 10.1016/j.ejmech.2019.07.044.
Zhi Huang 1,  Borui Zhao 2,  Zhongxiang Qin 2,  Yongtao Li 2,  Tianqi Wang 2,  Wei Zhou 2,  Jianyu Zheng 3,  Shengyong Yang 4,  Yi Shi 5,  Yan Fan 6,  Rong Xiang 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China.
  • 2 Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China.
  • 3 State Key Laboratory and Institute of Elemento-Organic Chemistry, Collaborative Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin, 300071, China.
  • 4 Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
  • 5 Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yishi@nankai.edu.cn.
  • 6 Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China. Electronic address: yanfan@nankai.edu.cn.
  • 7 Department of Medicinal Chemistry, School of Medicine, Nankai University, 94 Weijin Road, Tianjin, 300071, China; 2011 Project Collaborative Innovation Center for Biotherapy of Ministry of Education, 94 Weijin Road, Tianjin, 300071, China; State Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, Tianjin, 300071, China. Electronic address: rxiang@nankai.edu.cn.
PMID: 31382120 DOI: 10.1016/j.ejmech.2019.07.044
Abstract

Based on the significantly synergistic effects of CDK4 and VEGFR2/KDR/Flk-1 inhibitors on growth of Cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2/KDR/Flk-1 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2/KDR/Flk-1 with half-maximal inhibitory concentration at the nanomolar level. It effectively induced breast and cervical Cancer cell cycle arrest and cell Apoptosis. Roxyl-ZV-5J also inhibited the proliferation, tube formation and VEGFR2/KDR/Flk-1 downstream signaling pathways of HUVECs. Oral administration of Roxyl-ZV-5J led to significant tumor regression and anti-angiogenesis without obvious toxicity in SiHa xenograft mouse model. In addition, this compound showed good pharmacokinetics. This study confirmed a new tool for dual CDK-VEGFR2 pathways inhibition achieved with a single molecule, which provided valuable leads for further structural optimization and anti-angiogenesis and anti-tumor mechanism study.

Keywords

CDK4; Cancer; Inhibitor; VEGFR2.

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