106 Beta-3 integrin inhibition reduces inflammatory cytokine release but not anti-cancer activity of oncolytic adenovirus in ovarian cancer

Abstract

proteins, and a library of 87,000 diverse lead-like molecules was screened. NFK GreenTM was also used to determine the tryptophan metabolizing activity in a collection of human cancer cell lines and was related to the expression levels of IDO1 and TDO by western blot analysis. Results: Biochemical and cell-based screening assays were developed for IDO1 and TDO using a new fluorescent read-out. High-throughput screening of libraries of small chemical compound libraries yielded novel selective inhibitors of either IDO1 or TDO. Side-by-side comparison of published reference compounds revealed significant, previously unnoted cross-reactivity of a widely used hydroxyamidine-based inhibitor of IDO1 (Compound 5l) with TDO. The selectivity of other reference IDO1 or TDO inhibitors was confirmed, leading to definition of a new tool compound set. Biochemical selectivity of compounds correlated with inhibition of cellular tryptophan metabolizing activity and expression of IDO1 or TDO. Conclusions: We have developed new biochemical and cell-based assays for IDO1 and TDO, to enable the identification of novel small molecule inhibitors and to support lead optimization. Side-by-side comparison of published inhibitors revealed novel, unanticipated cross-reactivity of IDO1 inhibitor scaffolds with TDO.