In several human cancers, increased production of the tryptophan metabolite kynurenine by the enzymes indoleamine 2,3-dioxygenase (IDO1) and tryptophan 2,3-dioxygenase (TDO) creates a tolerogenic environment that promotes tumor driven immune suppression. One or both of these enzymes is up-regulated in a number of immune cells and in approximately 50% of human tumors (Pilotte et al., 2012). We have designed and synthesized novel inhibitors of IDO1 and dual inhibitors of IDO1 and TDO (PCT/US14/24920) that inhibit IDO1 in vitro and drop kynurenine production in established human cellular models of IDO1 (IFNγ treated HeLa cells) and/or TDO (A172 glioblastoma cells) and enhance T cell proliferation in a mixed culture assay. Further, these molecules cause a steep and durable reduction in plasma kynurenine in LPS treated c57/Bl6 mice, demonstrating inverse correlation between drug and kynurenine levels. In order to evaluate their therapeutic potential we monitored tumor penetration by the compounds and concomitant tumor kynurenine reduction in Balb/c mice implanted with the murine colon carcinoma CT-26 cell line. Several compounds drastically reduced tumor kynurenine levels compared to vehicle treated animals. One such compound, Compound 1, was further evaluated for its ability to reduce tumor burden both as monotherapy and in combination with doxorubicin. Currently we have nominated candidate compounds which are either IDO1 specific or IDO1/TDO dual inhibitors for regulatory toxicology.
Citation Format: Monali Banerjee, Sandip Middya, Ritesh Shrivastava, Sushil Raina, Dharmendra Yadav, Satveer Singh, Anindita Manna, Debjani Chakraborty, Arjun Surya. Novel inhibitors of human IDO1 and TDO. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A59.
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