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
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 f...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Chemical Society
2017
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| _version_ | 1797082085094064128 |
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| author | 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 Négrerie, M Maegley, K Miller, N Murray, BW Schneider, M Soloweij, J Stewart, AE Tumang, J Torti, VR Van Den Eynde, B Wythes, M |
| author_facet | 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 Négrerie, M Maegley, K Miller, N Murray, BW Schneider, M Soloweij, J Stewart, AE Tumang, J Torti, VR Van Den Eynde, B Wythes, M |
| author_sort | Crosignani, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T01:23:13Z |
| format | Journal article |
| id | oxford-uuid:9110a222-b5ef-4b52-adea-6a4da2073d31 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:23:13Z |
| publishDate | 2017 |
| publisher | American Chemical Society |
| record_format | dspace |
| spelling | oxford-uuid:9110a222-b5ef-4b52-adea-6a4da2073d312022-03-26T23:16:08ZDiscovery 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 candidateJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9110a222-b5ef-4b52-adea-6a4da2073d31EnglishSymplectic Elements at OxfordAmerican Chemical Society2017Crosignani, SBingham, PBottemanne, PCannelle, HCauwenberghs, SCordonnier, MDalvie, DDeroose, FFeng, JLGomes, BGreasley, SKaiser, SEKraus, MNégrerie, MMaegley, KMiller, NMurray, BWSchneider, MSoloweij, JStewart, AETumang, JTorti, VRVan Den Eynde, BWythes, MTumors 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. |
| spellingShingle | 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 Négrerie, M Maegley, K Miller, N Murray, BW Schneider, M Soloweij, J Stewart, AE Tumang, J Torti, VR 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 |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
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