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

• DOI: 10.1016/j.ejmech.2019.07.044
• Publication Date: 2019-07-28T01:07:11Z
• Authors: Zhi Huang; Borui Zhao; Zhongxiang Qin; Yongtao Li; Tianqi Wang; Wei Zhou; Jianyu Zheng; Shengyong Yang; Yi Shi; Yan Fan; Rong Xiang
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Dose-Response Relationship, Drug; Molecular Structure; Cell Survival; Aminopyridines; Cyclin-Dependent Kinase 4; Antineoplastic Agents; Mice, SCID; Neoplasms, Experimental; 3. Good health; Mice; 03 medical and health sciences; Mice, Inbred NOD; Cell Line, Tumor; Human Umbilical Vein Endothelial Cells; Animals; Humans; Anilides; Benzimidazoles; Female; Drug Screening Assays, Antitumor; Cell Proliferation

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.