abemaciclib and cabozantinib

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.

Topics: Aminopyridines; Anilides; Animals; Antineoplastic Agents; Benzimidazoles; Cell Line, Tumor; Cell Proliferation; Cell Survival; Cyclin-Dependent Kinase 4; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Human Umbilical Vein Endothelial Cells; Humans; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Neovascularization, Pathologic; Protein Kinase Inhibitors; Pyridines; Structure-Activity Relationship; Vascular Endothelial Growth Factor Receptor-2