7M63

Crystal structure of the indoleamine 2,3-dioxygenagse 1 (IDO1) complexed with IACS-70099

7M63 の概要

• エントリーDOI: 10.2210/pdb7m63/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, (2R)-N-(4-chlorophenyl)-2-[(1R,3S,5S,6r)-3-(5,6-difluoro-1H-benzimidazol-1-yl)bicyclo[3.1.0]hexan-6-yl]propanamide (2 entities in total)
• 機能のキーワード: ido1, inhibitor, enzyme, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 93422.24

構造登録者

Leonard, P.G.,Cross, J.B. (登録日: 2021-03-25, 公開日: 2021-09-01, 最終更新日: 2024-10-23)

主引用文献

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

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: 34292726
DOI: 10.1021/acs.jmedchem.1c00679

実験手法

X-RAY DIFFRACTION (3.1 Å)