Antiangiogenic properties of the IMPDH inhibitor AVN944

3983 AVN944 is an orally bioavailable inhibitor of inosine monophosphate dehydrogenase 1 and 2 (IMPDH). IMPDH2 is the rate limiting enzyme for the de novo production of guanine nucleotides, and is highly up-regulated in many malignancies, including hematologic cancers. AVN944 has been shown to be a potent inhibitor of cancer cell proliferation, and to elicit a specific set of cellular responses directly related to depletion of cellular GTP pools (Strovel et al., 2006). Recent reports (Chong et al., 2006) have suggested that IMPDH inhibition could provide added benefit as a cancer therapy through blockade of tumor angiogenesis. To investigate this hypothesis, we evaluated AVN944 in a series of angiogenesis assays to determine the potential utility of this drug as an antiangiogenic agent for cancer treatment. AVN944 was found to potently inhibit endothelial cell proliferation, with an IC50 of approximately 30nM, significantly more potent than the IMPDH inhibitor mycophenolic acid (MPA; 130nM). Other in vitro assessments of AVN944 activity in endothelial cells included a comprehensive analysis of global gene expression changes resulting from IMPDH inhibition in these cells. The pathways and genes affected by IMPDH inhibition in endothelial cells were compared to those affected by AVN944 treatment of cancer cells, in an attempt to distinguish the reported dependence of endothelial cells on IMPDH 1 versus 2. Even more specifically, a broad set of biomarkers, currently being used to monitor response in patient samples from a phase I clinical trial with AVN944, was analyzed to assess the similarity of the response of endothelial cells to GTP depletion, as compared to cancer cells and patient samples. In addition, AVN944 antiangiogenesis activity was analyzed in the in vivo matrigel plug assay and in a renal carcinoma xenograft model. These results, detailing the potent inhibition of endothelial cells in vitro combined with inhibition of angiogenesis in relevant in vivo models, could position this drug for rapid development as a novel antiangiogenic agent for cancer therapy.