Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and th...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | Journal of Enzyme Inhibition and Medicinal Chemistry |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/14756366.2022.2089665 |
| _version_ | 1828723126664429568 |
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| author | Ute F. Röhrig Somi Reddy Majjigapu Pierre Vogel Aline Reynaud Florence Pojer Nahzli Dilek Patrick Reichenbach Kelly Ascenção Melita Irving George Coukos Olivier Michielin Vincent Zoete |
| author_facet | Ute F. Röhrig Somi Reddy Majjigapu Pierre Vogel Aline Reynaud Florence Pojer Nahzli Dilek Patrick Reichenbach Kelly Ascenção Melita Irving George Coukos Olivier Michielin Vincent Zoete |
| author_sort | Ute F. Röhrig |
| collection | DOAJ |
| description | The haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and therefore IDO1 inhibitors have been developed for use in anti-cancer immunotherapy. Here, we report an extension of our previously described highly efficient haem-binding 1,2,3-triazole and 1,2,4-triazole inhibitor series, the best compound having both enzymatic and cellular IC50 values of 34 nM. We provide enzymatic inhibition data for almost 100 new compounds and X-ray diffraction data for one compound in complex with IDO1. Structural and computational studies explain the dramatic drop in activity upon extension to pocket B, which has been observed in diverse haem-binding inhibitor scaffolds. Our data provides important insights for future IDO1 inhibitor design. |
| first_indexed | 2024-04-12T12:45:26Z |
| format | Article |
| id | doaj.art-cf28d46a56e84bc6b249d5272612f6f4 |
| institution | Directory Open Access Journal |
| issn | 1475-6366 1475-6374 |
| language | English |
| last_indexed | 2024-04-12T12:45:26Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Journal of Enzyme Inhibition and Medicinal Chemistry |
| spelling | doaj.art-cf28d46a56e84bc6b249d5272612f6f42022-12-22T03:32:38ZengTaylor & Francis GroupJournal of Enzyme Inhibition and Medicinal Chemistry1475-63661475-63742022-12-013711773181110.1080/14756366.2022.2089665Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitorsUte F. Röhrig0Somi Reddy Majjigapu1Pierre Vogel2Aline Reynaud3Florence Pojer4Nahzli Dilek5Patrick Reichenbach6Kelly Ascenção7Melita Irving8George Coukos9Olivier Michielin10Vincent Zoete11SIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandSIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandLaboratory of Glycochemistry and Asymmetric Synthesis, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandProtein Production and Structure Core Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandProtein Production and Structure Core Facility, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, SwitzerlandSIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandDepartment of Oncology UNIL-CHUV, Ludwig Lausanne Branch, Epalinges, SwitzerlandSIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandDepartment of Oncology UNIL-CHUV, Ludwig Lausanne Branch, Epalinges, SwitzerlandDepartment of Oncology UNIL-CHUV, Ludwig Lausanne Branch, Epalinges, SwitzerlandSIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandSIB Swiss Institute of Bioinformatics, Molecular Modeling Group, Lausanne, SwitzerlandThe haem enzyme indoleamine 2,3-dioxygenase 1 (IDO1) catalyses the rate-limiting step in the kynurenine pathway of tryptophan metabolism and plays an essential role in immunity, neuronal function, and ageing. Expression of IDO1 in cancer cells results in the suppression of an immune response, and therefore IDO1 inhibitors have been developed for use in anti-cancer immunotherapy. Here, we report an extension of our previously described highly efficient haem-binding 1,2,3-triazole and 1,2,4-triazole inhibitor series, the best compound having both enzymatic and cellular IC50 values of 34 nM. We provide enzymatic inhibition data for almost 100 new compounds and X-ray diffraction data for one compound in complex with IDO1. Structural and computational studies explain the dramatic drop in activity upon extension to pocket B, which has been observed in diverse haem-binding inhibitor scaffolds. Our data provides important insights for future IDO1 inhibitor design.https://www.tandfonline.com/doi/10.1080/14756366.2022.2089665Cancer immunotherapystructure-based drug designtryptophan metabolismX-ray crystallography |
| spellingShingle | Ute F. Röhrig Somi Reddy Majjigapu Pierre Vogel Aline Reynaud Florence Pojer Nahzli Dilek Patrick Reichenbach Kelly Ascenção Melita Irving George Coukos Olivier Michielin Vincent Zoete Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors Journal of Enzyme Inhibition and Medicinal Chemistry Cancer immunotherapy structure-based drug design tryptophan metabolism X-ray crystallography |
| title | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
| title_full | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
| title_fullStr | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
| title_full_unstemmed | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
| title_short | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
| title_sort | structure based optimization of type iii indoleamine 2 3 dioxygenase 1 ido1 inhibitors |
| topic | Cancer immunotherapy structure-based drug design tryptophan metabolism X-ray crystallography |
| url | https://www.tandfonline.com/doi/10.1080/14756366.2022.2089665 |
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