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

  • J Med Chem. 2021 Aug 12;64(15):11302-11329. doi: 10.1021/acs.jmedchem.1c00679.
Matthew M Hamilton  1 ,  Faika Mseeh  1 ,  Timothy J McAfoos  1 ,  Paul G Leonard  1 ,  Naphtali J Reyna  1 ,  Angela L Harris  2 ,  Alan Xu  1 ,  Michelle Han  1 ,  Michael J Soth  1 ,  Barbara Czako  1 ,  Jay P Theroff  1 ,  Pijus K Mandal  1 ,  Jason P Burke  1 ,  Brett Virgin-Downey  1 ,  Alessia Petrocchi  1 ,  Dana Pfaffinger  1 ,  Norma E Rogers  1 ,  Connor A Parker  1 ,  Simon S Yu  1 ,  Yongying Jiang  1 ,  Stephan Krapp  3 ,  Alfred Lammens  3 ,  Graham Trevitt  4 ,  Martin R Tremblay  5 ,  Keith Mikule  5 ,  Keith Wilcoxen  5 ,  Jason B Cross  1 ,  Philip Jones  1 ,  Joseph R Marszalek  2 ,  Richard T Lewis  1
Affiliations
  • 1. IACS (Institute for Applied Cancer Science), University of Texas, MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 2. TRACTION (Translational Research to Advance Therapeutics and Innovation in Oncology), University of Texas, MD Anderson Cancer Center, 1881 East Road, Houston, Texas 77054, United States.
  • 3. Proteros Biostructures GmbH, Bunsenstr. 7a, D-82152 Martinsried, Germany.
  • 4. XenoGesis Ltd, BioCity Nottingham, Pennyfoot Street, Nottingham, Nottinghamshire NG1 1GF, U.K.
  • 5. Tesaro Inc., 1000 Winter Street, Waltham, Massachusetts 02451 United States.
PMID: 34292726 DOI: 10.1021/acs.jmedchem.1c00679
Abstract

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.

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