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

Matthew M HamiltonFaika MseehTimothy J McAfoosPaul G LeonardNaphtali J ReynaAngela L HarrisAlan XuMichelle HanMichael J SothBarbara CzakoJay P TheroffPijus K MandalJason P BurkeBrett Virgin-DowneyAlessia PetrocchiDana PfaffingerNorma E RogersConnor A ParkerSimon S YuYongying JiangStephan KrappAlfred LammensGraham TrevittMartin R TremblayKeith MikuleKeith WilcoxenJason B CrossPhilip JonesJoseph R MarszalekRichard T Lewis
Published in: Journal of medicinal chemistry (2021)
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.
Keyphrases
  • endothelial cells
  • induced pluripotent stem cells
  • pluripotent stem cells
  • high throughput
  • palliative care
  • stem cells
  • magnetic resonance imaging
  • high resolution
  • mass spectrometry
  • drug delivery
  • risk assessment