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

• Published in: Cancer science 2012-05, Vol.103 (5), p.939-944
• Main Authors: Awazu, Yoshiko, Mizutani, Akio, Nagase, Yoshinori, Iwata, Hidehisa, Oguro, Yuya, Miki, Hiroshi, Imamura, Shinichi, Hori, Akira
• Format: Article
• Language: English
• Subjects: Angiogenesis; Angiogenesis Inhibitors - therapeutic use; Animals; Antitumor activity; Bridged Bicyclo Compounds, Heterocyclic - therapeutic use; Cancer; Cell Line, Tumor; Cell proliferation; Cells, Cultured; coronary artery; Endothelial cells; Fibroblasts; Humans; Irinotecan; Mice; Mice, Nude; Mice, SCID; Neoplasms - blood supply; Neoplasms - drug therapy; Original; pericytes; Phenylurea Compounds - therapeutic use; Phosphorylation; Platelet-derived growth factor receptors; Pressure; Protein-tyrosine kinase; Receptors, Platelet-Derived Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Smooth muscle; Solid tumors; Survival; Tumors; Vascular endothelial growth factor receptors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2012.02238.x

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 (IC50 = 2.5 and 3.6 nM, respectively) and proliferation of HUVECs and human coronary artery smooth muscle cells with IC50 values of 2.8 and 9.6 nM, respectively, and potently inhibits the VEGF‐induced tube formation of endothelial cells cocultured with fibroblasts (IC50 = 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. (Cancer Sci 2012; 103: 939–944)