5whr

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

spinqualitylabelsall models 5whr, resolution 2.28Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5whr is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.28Å Ligands: AOJ, HEM Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function I23O1_HUMAN Catalyzes the cleavage of the pyrrol ring of tryptophan and incorporates both atoms of a molecule of oxygen. Publication Abstract from PubMed 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. 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.,Crosignani S, Bingham P, Bottemanne P, Cannelle H, Cauwenberghs S, Cordonnier M, Dalvie D, Deroose F, Feng JL, Gomes B, Greasley S, Kaiser SE, Kraus M, Negrerie M, Maegley K, Miller N, Murray BW, Schneider M, Soloweij J, Stewart AE, Tumang J, Torti VR, Van Den Eynde B, Wythes M J Med Chem. 2017 Dec 14;60(23):9617-9629. doi: 10.1021/acs.jmedchem.7b00974. Epub, 2017 Nov 21. PMID:29111717 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Dioxygenase 3D structures

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