Indoleamine-2,3-dioxygenase-1 (IDO1) is a heme-containing enzyme which catalyzes the catabolism of tryptophan (Trp) via dioxygenation to produce N-formyl kynurenine, which is further processed to produce immunosuppressive catabolites such as kynurenine (Kyn). As such, IDO1 plays a central role in peripheral immune tolerance and is upregulated in instances of inflammation. Many human tumors have been shown to exploit this pathway by constitutively expressing 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. The recent PhIII failure of this combination to show improved efficacy over anti-PD-1 monotherapy (ECHO-301/KEYNOTE-252) has prompted speculation that epacadostat may have failed to achieve sufficient target engagement in the tumor microenvironment. In order to unequivocally test the clinical utility of IDO1 inhibition in combination with anti-PD-1 antibodies, it is highly desirable to discover potent IDO1 inhibitors with improved selectivity to allow for dosing to achieve higher levels of target engagement.<br/>   This presentation will elaborate on the previously-disclosed discovery of several classes of heme-displacing inhibitors of IDO1, and will specifically highlight the evolution of a class of diamide-containing screening hits to provide compounds that demonstrate exquisitely potent IDO1 inhibition in a whole blood assay and which possess excellent pharmacokinetic (PK) profiles in preclinical species. The optimization of this series was guided by structure-based drug design, with a focus on addressing key routes of metabolism and optimizing physicochemical properties to deliver compounds with lower predicted human dose and devoid of significant off-target liabilities.

Discovery and evolution of potent and selective heme-displacing IDO1 inhibitors

2019 Fall National Meeting

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