The clinical successes of VEGF-targeted agents in recent years have demonstrated that antiangiogenic therapy can be developed as effective anti-cancer treatment. However, the field of oncology is facing a new challenge of overcoming the resistance to VEGF-targeted therapy; therefore, novel angiogenesis inhibitors are required for new therapeutic development. During the growth of new blood capillaries, following proliferation and migration, endothelial cells undergo morphological changes and adhere to each other forming tubular structures as a process of tubulogenesis, which presents a unique target for inhibitory action of antiangiogenic agents. Southern Research angiogenesis research team has identified a structurally related series of heterocyclic compounds SRI-24637 and its analogs as a new class of antiangiogenic agents. SRI-24637 demonstrated selective potent inhibition of endothelial tube-formation and significant activity in blocking tumor-induced blood vessel formation using an ex vivo human cancer xenograft-CAM assay model system. The mechanism of action of SRI-24637 is different from the clinical VEGF-targeted drugs; therefore, it may provide a complementary mechanism to overcome the resistance to VEGF-targeted therapies. Bioavailability studies showed that SRI-24637 dosed at 40 mg/kg in DMSO/PEG400 reached systemic concentration levels much higher than the IC50 concentration for in vitro endothelial tube-formation. Comparing with the clinical VEGF-targeted drug Sunitinib, the cytotoxic activities of SRI-24637 against normal human fibroblast and epithelial cells suggest that the toxic side effects of SRI-24637 may be within a tolerable range. Ongoing preclinical efficacy studies with animal tumor models will aid in the development of SRI-24637 as an anti-cancer drug. Based on the outcome of these studies, further lead optimization will be done if required, before entering it into the clinical Phase I and II trials using protocols similar to those employed for Sunitinib and Sorafenib, or other investigational small molecules targeting tumor angiogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5474.