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.
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.
Oncology Drug Discovery Unit, Takeda Pharmaceutical Company Limited, Fujisawa, Japan.
Yoshiko
Y
Awazu
Akio
A
Mizutani
Yoshinori
Y
Nagase
Hidehisa
H
Iwata
Yuya
Y
Oguro
Hiroshi
H
Miki
Shinichi
S
Imamura
Akira
A
Hori
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
C555239:1-(2-fluoro-4-((5-methyl-5H-pyrrolo(3,2-d)pyrimidin-4-yl)oxy)phenyl)-3-(3-(trifluoromethyl)phenyl)urea; D020533:Angiogenesis Inhibitors; D019086:Bridged Bicyclo Compounds, Heterocyclic; D010671:Phenylurea Compounds; C099852:PDGF receptor tyrosine kinase; D017479:Receptors, Platelet-Derived Growth Factor; D040262:Receptors, Vascular Endothelial Growth Factor