Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

Details

Serval ID
serval:BIB_EF494F840FDA
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Structure-based optimization of type III indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.
Journal
Journal of enzyme inhibition and medicinal chemistry
Author(s)
Röhrig U.F., Majjigapu S.R., Vogel P., Reynaud A., Pojer F., Dilek N., Reichenbach P., Ascenção K., Irving M., Coukos G., Michielin O., Zoete V.
ISSN
1475-6374 (Electronic)
ISSN-L
1475-6366
Publication state
Published
Issued date
12/2022
Peer-reviewed
Oui
Volume
37
Number
1
Pages
1773-1811
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
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 IC <sub>50</sub> 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.
Keywords
Cancer immunotherapy, X-ray crystallography, structure-based drug design, tryptophan metabolism
Pubmed
Create date
28/06/2022 8:09
Last modification date
15/07/2022 6:35
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