Abstract 1633: Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy

Abstract

Abstract Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase is an central immune checkpoint mechanism that controls peripheral immune tolerance and tumor resistance to immune attack. The IDO pathway mediates immunosuppressive effects by expression of the IDO1 gene by tumor cells and/or host antigen presenting cells. Tryptophan depletion and generation of kynurenine generate downstream signals through GCN2, WARS, mTOR and AHR that ultimately lead to anergy of tumor-specific effector CD8+ T cells and activation of Tregs. High expression of IDO correlates negatively with clinical prognosis in patients with a variety of malignancies. Recently, it has been described that tumors can also achieve immunosuppressive effects mediated by tryptophan degradation through expression of TDO, an enzyme functionally and structurally related to IDO1. Therefore, development of small molecules that can prevent tryptophan degradation mediated by IDO1, TDO or both is a prime goal for immunotherapy of cancer. Here we report the discovery of a novel class of imidazoisoindole-based compounds that show potent and selective inhibition of TDO and IDO1, as well as compounds that show potent dual inhibition of both TDO and IDO1. We present structure-activity relationship studies that explore the molecular determinants of potency and specificity for TDO and IDO1. Compounds of these classes were tested for activity in in vitro assays using purified recombinant human and murine TDO and IDO1 as well as in cells expressing IDO1 or TDO. Many of these compounds are 10-200 fold more potent (IC50 < 50 nM) than previously published TDO-specific inhibitors. The pharmacokinetic properties of these compounds are being investigated and lead optimization efforts are in progress. Citation Format: Mario R. Mautino, Richard A. Metz, Firoz Jaipuri, Jesse Waldo, Sanjeev Kumar, Agnieszka Marcinowicz-Flick, Hima Potturi, James T. Adams, Clarissa Van Allen, Nicholas N. Vahanian, Charles J. Link. Novel specific- and dual- tryptophan-2,3-dioxygenase (TDO) and indoleamine-2,3-dioxygenase (IDO) inhibitors for tumor immunotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1633. doi:10.1158/1538-7445.AM2014-1633