7B1O
Crystal structure of the indoleamine 2,3-dioxygenase 1 (IDO1) in complex with compound 22
Summary for 7B1O
| Entry DOI | 10.2210/pdb7b1o/pdb |
| Descriptor | Indoleamine 2,3-dioxygenase 1, 4-chloranyl-N-[(1R)-1-[(1S,5R)-3-quinolin-4-yloxy-6-bicyclo[3.1.0]hexanyl]propyl]benzamide (3 entities in total) |
| Functional Keywords | enzyme, immunosuppressant |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 93169.99 |
| Authors | Lammens, A.,Krapp, S.,Lewis, R.T.,Hamilton, M.M. (deposition date: 2020-11-25, release date: 2021-09-29, Last modification date: 2024-10-23) |
| Primary citation | Hamilton, M.M.,Mseeh, F.,McAfoos, T.J.,Leonard, P.G.,Reyna, N.J.,Harris, A.L.,Xu, A.,Han, M.,Soth, M.J.,Czako, B.,Theroff, J.P.,Mandal, P.K.,Burke, J.P.,Virgin-Downey, B.,Petrocchi, A.,Pfaffinger, D.,Rogers, N.E.,Parker, C.A.,Yu, S.S.,Jiang, Y.,Krapp, S.,Lammens, A.,Trevitt, G.,Tremblay, M.R.,Mikule, K.,Wilcoxen, K.,Cross, J.B.,Jones, P.,Marszalek, J.R.,Lewis, R.T. Discovery of IACS-9779 and IACS-70465 as Potent Inhibitors Targeting Indoleamine 2,3-Dioxygenase 1 (IDO1) Apoenzyme. J.Med.Chem., 64:11302-11329, 2021 Cited by PubMed 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 () and IACS-70465 (). 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. PubMed: 34292726DOI: 10.1021/acs.jmedchem.1c00679 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.58 Å) |
Structure validation
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