ITOC2 – 013. In vitro kynurenine modulation by novel dual-acting and selective TDO and IDO inhibitors

Abstract

<h3>Background</h3> TDO (tryptophan 2,3-dioxygenase) and IDO (indoleamine 2,3-dioxygenase) catalyse the oxidation of tryptophan leading to the formation of immunesuppressive kynurenine pathway (KP) metabolites and dampening the immune response in the tumour environment. IDO is up-regulated in numerous cancers. Recently, TDO was shown to be up-regulated in various tumour types. Hence, selective IDO inhibitors may have a limited effect in cancers harbouring both TDO and IDO. To test this hypothesis we utilised novel dual-active and selective TDO/IDO inhibitors to modulate kynurenine (Kyn) levels in cells expressing TDO alone and both TDO and IDO. <h3>Methods</h3> Assays were developed to measure the effects of dual and selective TDO/IDO inhibitors on Kyn levels in A172 glioma cells expressing TDO alone or both TDO and IDO following IDO induction using Interferon (IFNg). <h3>Findings</h3> Dual-active and selective TDO/IDO inhibitors demonstrated distinct Kyn modulating activities in A172 cells expressing TDO alone or both TDO and IDO (Fig. 1). Dual-active molecules ablated Kyn levels in both TDO-only and TDO/IDO-expressing cells. IDO selective inhibitors were more active in cells following IDO induction. TDO inhibitors were more active in TDO-only cells. Selective inhibitors did not fully block Kyn in cells expressing IDO and TDO. <h3>Discussion</h3> These data demonstrate that dual-active TDO/IDO inhibitors are most effective at ablating Kyn levels in cancer cells co-expressing TDO and IDO.