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.
- 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: [email protected].
- 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: [email protected].
- 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: [email protected].
Based on the significantly synergistic effects of CDK4 and VEGFR2 inhibitors on growth of Cancer cells, a series of novel multi-kinase inhibitors targeting CDK4 and VEGFR2 were designed, synthesized and evaluated, among which Roxyl-ZV-5J exhibited potent and balanced activities against both CDK4 and VEGFR2 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 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.