Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme

Indoleamine
2,3-dioxygenase 1 (IDO1), a heme-containing enzyme
that mediates the rate-limiting step in the metabolism of l-tryptophan to kynurenine, has been widely explored as a potential
immunotherapeutic target in oncology. We developed a class of inhibitors
with a conformationally constrained bicyclo[3.1.0]­hexane core. These
potently inhibited IDO1 in a cellular context by binding to the apoenzyme,
as elucidated by biochemical characterization and X-ray crystallography.
A SKOV3 tumor model was instrumental in differentiating compounds,
leading to the identification of IACS-9779 (62) and IACS-70465
(71). IACS-70465 has excellent cellular potency, a robust
pharmacodynamic response, and in a human whole blood assay was more
potent than linrodostat (BMS-986205). IACS-9779 with a predicted human
efficacious once daily dose below 1 mg/kg to sustain >90% inhibition
of IDO1 displayed an acceptable safety margin in rodent toxicology
and dog cardiovascular studies to support advancement into preclinical
safety evaluation for human development.