1区 · 医学
Article
作者: Tremblay, Martin R. ; Jiang, Yongying ; Han, Michelle ; Cross, Jason B. ; McAfoos, Timothy J. ; Reyna, Naphtali J. ; Mseeh, Faika ; Hamilton, Matthew M. ; Petrocchi, Alessia ; Yu, Simon S. ; Leonard, Paul G. ; Soth, Michael J. ; Marszalek, Joseph R. ; Pfaffinger, Dana ; Mikule, Keith ; Trevitt, Graham ; Harris, Angela L. ; Jones, Philip ; Czako, Barbara ; Krapp, Stephan ; Xu, Alan ; Wilcoxen, Keith ; Lammens, Alfred ; Lewis, Richard T. ; Mandal, Pijus K. ; Parker, Connor A. ; Theroff, Jay P. ; Virgin-Downey, Brett ; Burke, Jason P. ; Rogers, Norma E.
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.