7M7D
Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with IACS-8968
Summary for 7M7D
| Entry DOI | 10.2210/pdb7m7d/pdb |
| Related | 7M63 |
| Descriptor | Indoleamine 2,3-dioxygenase 1, (5S)-6,6-dimethyl-8-[(4S)-7-(trifluoromethyl)imidazo[1,5-a]pyridin-5-yl]-1,3,8-triazaspiro[4.5]decane-2,4-dione, PROTOPORPHYRIN IX CONTAINING FE, ... (4 entities in total) |
| Functional Keywords | ido1, inhibitor, enzyme, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 2 |
| Total formula weight | 94586.19 |
| Authors | Leonard, P.G.,Cross, J.B. (deposition date: 2021-03-27, release date: 2021-09-01, Last modification date: 2024-10-30) |
| 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 (2.6 Å) |
Structure validation
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