5WHR

Discovery of a novel and selective IDO-1 inhibitor PF-06840003 and its characterization as a potential clinical candidate.

5WHR の概要

• エントリーDOI: 10.2210/pdb5whr/pdb
• 分子名称: Indoleamine 2,3-dioxygenase 1, PROTOPORPHYRIN IX CONTAINING FE, (3R)-3-(5-fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione, ... (4 entities in total)
• 機能のキーワード: cancer immunotherapy, small molecule inhibitor, oxidoreductase, oxidoreductase-inhibitor complex, oxidoreductase/inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol : P14902
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 90033.00

構造登録者

Greasley, S.E.,Kaiser, S.E.,Feng, J.L.,Stewart, A. (登録日: 2017-07-18, 公開日: 2017-12-27, 最終更新日: 2024-10-09)

主引用文献

Crosignani, S.,Bingham, P.,Bottemanne, P.,Cannelle, H.,Cauwenberghs, S.,Cordonnier, M.,Dalvie, D.,Deroose, F.,Feng, J.L.,Gomes, B.,Greasley, S.,Kaiser, S.E.,Kraus, M.,Negrerie, M.,Maegley, K.,Miller, N.,Murray, B.W.,Schneider, M.,Soloweij, J.,Stewart, A.E.,Tumang, J.,Torti, V.R.,Van Den Eynde, B.,Wythes, M.
Discovery of a Novel and Selective Indoleamine 2,3-Dioxygenase (IDO-1) Inhibitor 3-(5-Fluoro-1H-indol-3-yl)pyrrolidine-2,5-dione (EOS200271/PF-06840003) and Its Characterization as a Potential Clinical Candidate.
J. Med. Chem., 60:9617-9629, 2017

PubMed Abstract: Tumors use tryptophan-catabolizing enzymes such as indoleamine 2,3-dioxygenase (IDO-1) to induce an immunosuppressive environment. IDO-1 is induced in response to inflammatory stimuli and promotes immune tolerance through effector T-cell anergy and enhanced Treg function. As such, IDO-1 is a nexus for the induction of a key immunosuppressive mechanism and represents an important immunotherapeutic target in oncology. Starting from HTS hit 5, IDO-1 inhibitor 6 (EOS200271/PF-06840003) has been developed. The structure-activity relationship around 6 is described and rationalized using the X-ray crystal structure of 6 bound to human IDO-1, which shows that 6, differently from most of the IDO-1 inhibitors described so far, does not bind to the heme iron atom and has a novel binding mode. Clinical candidate 6 shows good potency in an IDO-1 human whole blood assay and also shows a very favorable ADME profile leading to favorable predicted human pharmacokinetic properties, including a predicted half-life of 16-19 h.

PubMed: 29111717
DOI: 10.1021/acs.jmedchem.7b00974

実験手法

X-RAY DIFFRACTION (2.28 Å)