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

Matthew M. Hamilton, Faika Mseeh, Timothy J. McAfoos, Paul G. Leonard, Naphtali J. Reyna, Angela L. Harris, Alan Xu, Michelle Han, Michael J. Soth, Barbara Czako, Jay P. Theroff, Pijus K. Mandal, Jason P. Burke, Brett Virgin-Downey, Alessia Petrocchi, Dana Pfaffinger, Norma E. Rogers, Connor A. Parker, Simon S. Yu, Yongying JiangStephan Krapp, Alfred Lammens, Graham Trevitt, Martin R. Tremblay, Keith Mikule, Keith Wilcoxen, Jason B. Cross, Philip Jones, Joseph R. Marszalek, Richard T. Lewis

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)11302-11329
Number of pages28
JournalJournal of Medicinal Chemistry
Issue number15
StatePublished - Aug 12 2021
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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