Indoleamine-2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) are intracellular heme-containing enzymes which catalyze the first and rate-determining step in tryptophan (Trp) catabolism, producing immunosuppressive catabolites such as kynurenine (Kyn). Trp catabolism mediated by IDO1 is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance due to depletion of Trp levels in the tumoral microenvironment and the formation of immunosuppressive catabolites such as Kyn. Many human tumors are shown to constitutively express IDO1, and an increased level of IDO1 expression in tumor cells is correlated with poor prognosis for survival in several tumor types. Initial clinical POC for IDO1 inhibition in cancer was established with epacadostat, an IDO1 selective heme-binding inhibitor, in combination with anti-PD-1 antibodies in PhIb-II trials. However, in a PhIII confirmatory study (ECHO-301/KEYNOTE-252) in unresectable or metastatic melanoma, the epacadostat/pembrolizumab combo failed to show improved efficacy (PFS) over pembro monotherapy. While the underlying causes of the failure remain to be uncovered, there are a number of potential explanations, including insufficient tumor target engagement and the potential of AhR activation by epacadostat. In order to unequivocally test the clinical utility of IDO1 inhibition in combination with anti-PD-1 antibodies, it is highly desirable to discover exquisitely potent IDO1 inhibitors that are devoid of the potential for AhR activation, allowing an extremely high level of tumor target engagement without the complication of tumor immunosuppression <i>via</i> AhR activation.<br/>In this presentation, we will describe the identification of a number of heme-displacing IDO1 inhibitor hits from an ALIS screen, and subsequent structure based optimization of these hits to highly potent and structurally diverse IDO1 inhibitors with an excellent overall profile. We will also discuss the PK/PD behavior of representative inhibitors in a rodent tumor model in which a number of these inhibitors achieve unprecedented levels of IDO1 inhibition at low drug concentrations.

Discovery of potent and structurally diverse IDO1 selective heme-displacing inhibitors from optimization of hits from a mass spectrometry based affinity (ALIS) screen

2019 Spring National Meeting

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