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

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

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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