A novel pyrrolo[3, 2-d]pyrimidine derivative, as a vascular endothelial growth factor receptor and platelet-derived growth factor receptor tyrosine kinase inhibitor, shows potent antitumor activity by suppression of tumor angiogenesis.

Abstract

We recently reported that compound 20d (comp.20d), a novel pyrrolo[3, 2-d]pyrimidine derivative, is a potent and selective inhibitor of tumor angiogenesis-related kinases, including vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR). In this study, we show that comp.20d potently blocks the VEGF- and PDGF-stimulated cellular phosphorylation (IC(50) = 2.5 and 3.6 nM, respectively) and proliferation of HUVECs and human coronary artery smooth muscle cells with IC(50) values of 2.8 and 9.6 nM, respectively, and potently inhibits the VEGF-induced tube formation of endothelial cells cocultured with fibroblasts (IC(50) = 3.3 nM). Given orally twice daily, comp.20d at the doses of 1.5-6 mg/kg showed antitumor effects in mice bearing various human cancer xenografts. Consistent with the anti-angiogenic mechanism of action, histological examination of tumors from comp. 20d-treated mice indicated a decrease in microvessel density and inhibition of pericyte recruitment to microvessels, and these were concomitant with decreased interstitial fluid pressure that allowed for therapeutic intratumoral uptake of CPT-11 (irinotecan hydrochloride). In conclusion, comp.20d is an extremely potent inhibitor of VEGFR/PDGFR kinases whose activities suggest therapeutic potential for the treatment of solid tumors that rely on angiogenesis for their survival.

• Authors: Yoshiko Awazu, Akio Mizutani, Yoshinori Nagase, Hidehisa Iwata, Yuya Oguro, Hiroshi Miki, Shinichi Imamura, Akira Hori
• Journal: Cancer science (Cancer Sci) Vol. 103 Issue 5 Pg. 939-44 (May 2012) ISSN: 1349-7006 [Electronic] England
• PMID: 22320850 (Publication Type: Journal Article)
• Copyright: © 2012 Japanese Cancer Association and Takeda Pharmaceutical Company Limited.

Chemical References

• 1-(2-fluoro-4-((5-methyl-5H-pyrrolo(3,2-d)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea
• Angiogenesis Inhibitors
• Bridged Bicyclo Compounds, Heterocyclic
• Phenylurea Compounds
• PDGF receptor tyrosine kinase
• Receptors, Platelet-Derived Growth Factor
• Receptors, Vascular Endothelial Growth Factor

Topics

• Angiogenesis Inhibitors (therapeutic use)
• Animals
• Bridged Bicyclo Compounds, Heterocyclic (therapeutic use)
• Cell Line, Tumor
• Cells, Cultured
• Humans
• Mice
• Mice, Nude
• Mice, SCID
• Neoplasms (blood supply, drug therapy)
• Phenylurea Compounds (therapeutic use)
• Receptors, Platelet-Derived Growth Factor (antagonists & inhibitors)
• Receptors, Vascular Endothelial Growth Factor (antagonists & inhibitors)
• Xenograft Model Antitumor Assays