Abstract 5682: Design and preclinical evaluation of single agents with combination chemotherapy potential.

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Antiangiogenic agents target tumor mechanisms involved in blood vessel formation vital for tumor growth and metastases. However, these agents are mainly cytostatic and usually not tumoricidal. Several combinations of antiangiogenic and cytotoxic agents have shown significant promise in the clinic, and several clinical trials are in progress. Single agents with both antiangiogenic activities and cytotoxicity would afford agents that would circumvent pharmacokinetic problems of multiple agents, avoid drug-drug interactions, could be used at lower doses to alleviate toxicity, be devoid of overlapping toxicities, and could delay or prevent tumor cell resistance. We designed, synthesized and evaluated a novel compound AG119 that inhibits both vascular endothelial growth factor receptor-2 (VEGFR-2) affording antiangiogenic effects and tubulin for cytotoxic effects in a single agent. Structural modifications of AG119 afforded AG321 that inhibited platelet derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) in addition to VEGFR-2 and tubulin. The novel compounds AG119 and AG321 were potent inhibitors (activity comparable to that of combretastatin A-4) of bovine brain tubulin assembly and of [3H]colchicine binding to tubulin, indicating that these compounds bind at the colchicine site on tubulin. Both compounds have potency comparable to those of sunitinib and semaxinib in tumor cell lines overexpressing VEGFR-2. AG321 has potency comparable to that of erlotinib in tumor cell lines overexpressing EGFR and potency comparable to those of erlotinib, DMBI and PD153035 in cell lines overexpressing PDGFR-β. Both AG119 and AG321 also inhibited angiogenesis in the chorioallantoic membrane (CAM) assay. AG321 is a unique compound with four separate mechanisms of action in a single agent including inhibition of tubulin. This is unprecedented and to our knowledge, is the first of its kind. In mice, AG119 reduced tumor size and vascularity in two flank xenograft models [the BLBC MDA-MB-435 model and U251 glioma model] and in a 4T1 triple negative breast orthotopic allograft model. In these in vivo models, the activity of AG119 was superior to those of temozolomide (U251), docetaxel and sunitinib (MDA-MB-435 and 4T1) without overt toxicity to the animals. Citation Format: Aleem Gangjee, Roheeth K. Pavana, Michael A. Ihnat, Jessica E. Thorpe, Bryan C. Disch, Anja Bastian, Lora C. Bailey-Downs, Ernest Hamel, Rouli Bai. Design and preclinical evaluation of single agents with combination chemotherapy potential. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5682. doi:10.1158/1538-7445.AM2013-5682