Cancer Immunotherapy

NTRC has discovered a novel series of small molecule inhibitors of IDO1, an enzyme critically involved in the regulation of T cell response in cancer immunotherapy. The compound series was discovered by ultra-high throughput screening at the European Lead Factory using NFK Green™, an assay reagent developed at NTRC.

Many tumors use the tryptophan metabolizing enzymes IDO1 or TDO to induce an immunosuppressive environment that protects them against the host immune system. IDO1 is induced in response to inflammatory stimuli and promotes immune cell tolerance through T cell anergy and enhanced regulatory T cell function. Inhibitors of IDO1 have been shown to synergize with biologic inhibitors of immune check points, such as anti-PDL1 and anti-CTLA4, making IDO1 a prominent target in cancer immunotherapy.

To enable the identification of novel small molecule inhibitors of IDO1, NTRC scientists developed a chemical probe to detect the reaction product of the conversion of tryptophan by IDO1, N-formyl kynurenine (NFK) [1]. Reaction of the probe with NFK results in a green fluorescent product that can be measured on conventional fluorescence or multimode readers. NTRC scientists used the NFK Green™ assay to identify a novel chemical series of small molecule inhibitors of IDO1 at the European Lead Factory. The compounds are selective over TDO and effectively decreased the formation of tryptophan metabolites in tumors in in vivo experiments.

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Model of a reference inhibitor bound in the active site of IDO1.

NTRC publication on IDO1

[1] Seegers et al. (2014) High-throughput fluorescence-based screening assays for tryptophan-catabolizing enzymes. Journal of Biomolecular Screening 19, 1266-1274.

Current Projects

Cancer immunotherapy