Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
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| Titel: | Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors |
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| Autoren: | 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 |
| Quelle: | J Enzyme Inhib Med Chem Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 37, Iss 1, Pp 1773-1811 (2022) Journal of enzyme inhibition and medicinal chemistry, vol. 37, no. 1, pp. 1773-1811 |
| Verlagsinformationen: | Informa UK Limited, 2022. |
| Publikationsjahr: | 2022 |
| Schlagwörter: | 0301 basic medicine, Cancer immunotherapy, RM1-950, Heme, Triazoles, 01 natural sciences, 0104 chemical sciences, 3. Good health, 03 medical and health sciences, Enzyme Inhibitors/chemistry, Enzyme Inhibitors/pharmacology, Indoleamine-Pyrrole 2,3,-Dioxygenase, Triazoles/chemistry, Triazoles/pharmacology, X-ray crystallography, structure-based drug design, tryptophan metabolism, Therapeutics. Pharmacology, Enzyme Inhibitors, Research Paper |
| Beschreibung: | 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. |
| Publikationsart: | Article Other literature type |
| Dateibeschreibung: | application/pdf |
| Sprache: | English |
| ISSN: | 1475-6374 1475-6366 |
| DOI: | 10.1080/14756366.2022.2089665 |
| DOI: | 10.6084/m9.figshare.20159042.v1 |
| DOI: | 10.6084/m9.figshare.20159042 |
| Zugangs-URL: | https://pubmed.ncbi.nlm.nih.gov/35758198 https://doaj.org/article/cf28d46a56e84bc6b249d5272612f6f4 http://nbn-resolving.org/urn/resolver.pl?urn=urn:nbn:ch:serval-BIB_EF494F840FDA2 https://serval.unil.ch/resource/serval:BIB_EF494F840FDA.P001/REF.pdf https://serval.unil.ch/notice/serval:BIB_EF494F840FDA |
| Rights: | CC BY |
| Dokumentencode: | edsair.doi.dedup.....2189c16a257fd161d0250c38e4d08516 |
| Datenbank: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstract: | 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. |
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| ISSN: | 14756374 14756366 |
| DOI: | 10.1080/14756366.2022.2089665 |