Indoleamine 2,3-dioxygenase 1 (IDO1) is an inducible, heme-containing enzyme that catabolizes the essential amino acid tryptophan to kynurenine. Low levels of tryptophan result in suppression of cytotoxic T cell (CTL) proliferation, and elevated levels of downstream kynurenine metabolites have a cytotoxic effect on T cells. IDO1 is elevated in the tumor microenvironment of multiple cancers and correlates negatively with prognosis. Early clinical studies suggest that IDO1 inhibitors enhance the efficacy of anti-PD1 and anti-CTLA4 checkpoint inhibitors in melanoma and lung cancer. We initiated an IDO1 inhibitor program and during the course of our research, a novel mechanism of inhibition was discovered wherein binding of the heme cofactor to IDO1 is prevented by our inhibitors. Here in we describe our efforts towards the discovery of GS-4361, which had excellent potency, selectivity, and pharmacokinetic properties.

GS-4361: A novel IDO1 Inhibitor

2019 Spring National Meeting

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