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

Abstract

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.

• Authors: Zhi Huang, Borui Zhao, Zhongxiang Qin, Yongtao Li, Tianqi Wang, Wei Zhou, Jianyu Zheng, Shengyong Yang, Yi Shi, Yan Fan, Rong Xiang
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 181 Pg. 111541 (Nov 01 2019) ISSN: 1768-3254 [Electronic] France
• PMID: 31382120 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Masson SAS. All rights reserved.

Chemical References

• Aminopyridines
• Anilides
• Antineoplastic Agents
• Benzimidazoles
• Protein Kinase Inhibitors
• Pyridines
• cabozantinib
• abemaciclib
• KDR protein, human
• Vascular Endothelial Growth Factor Receptor-2
• CDK4 protein, human
• Cyclin-Dependent Kinase 4

Topics

• Aminopyridines (chemical synthesis, chemistry, pharmacology)
• Anilides (chemical synthesis, chemistry, pharmacology)
• Animals
• Antineoplastic Agents (chemical synthesis, chemistry, pharmacology)
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclin-Dependent Kinase 4 (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Screening Assays, Antitumor
• Female
• Human Umbilical Vein Endothelial Cells (drug effects)
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, SCID
• Molecular Structure
• Neoplasms, Experimental (drug therapy, metabolism, pathology)
• Neovascularization, Pathologic (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (chemical synthesis, chemistry, pharmacology)
• Pyridines (chemical synthesis, chemistry, pharmacology)
• Structure-Activity Relationship
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, metabolism)