Research Project
6792527
[unreadable] DESCRIPTION (provided by applicant): [unreadable] Up-regulation of vascular endothelial growth factor (VEGF), a key factor for angiogenesis, is an important contributor to the pathogenesis of cancers, diabetic retinopathy, and exudative macular degeneration. The abundance of VEGF is in large part controlled at the post-transcriptional level by sequences in both the 5'- and 3'-untranslated regions (UTRs) of its mRNA. The 5'-UTR contains an internal ribosomal entry site (IRES) that mediates a unique, cap-independent mode of translation initiation. Under hypoxic conditions, cap-dependent translation is dramatically impaired and the translation of the VEGF mRNA occurs through its cap-independent IRES. Thus, even under severe hypoxic conditions, cells are capable of producing large amounts of VEGF resulting in angiogenesis to support further tumor growth or aberrant neovascularization as occurs in ocular diseases. In addition, the 3'-UTR harbors multiple AU-rich stability determinants that have been previously shown to regulate VEGF mRNA turnover rates. Using PTC's proprietary technology platforms, we have successfully identified a collection of compounds that inhibit the expression of VEGF post transcriptionally. The initial results from medicinal chemistry efforts are very encouraging, since all three lead series identified contain compounds with low nanomolar activity for the inhibition of VEGF expression. Preliminary selectivity studies demonstrated that there is a subset of compounds that specifically inhibit VEGF production, while a second set of compounds inhibits VEGF expression as well as other angiogenesis factors such as FGF-2 expression. Based on these results, the aims of this proposal are to further [unreadable] characterize these compounds identified from HTS and preliminary SAR studies in a battery of selectivity assays and cytotoxicity assays; initiate structure-activity studies around the lead compounds to enhance potency, efficacy and selectivity; and develop end-point assays to measure the therapeutic efficacies of compounds for future studies in animals. [unreadable] [unreadable] [unreadable]
