Design, synthesis and evaluation of tryptophan analogues as tool compounds to study IDO1 activity.

Autor: Cundy NJ; School of Chemistry, University of Birmingham Edgbaston Birmingham B15 2TT UK r.s.grainger@bham.ac.uk., Hare RK; Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, University of Manchester Manchester M13 9PL UK., Tang T; Celentyx Ltd, Birmingham Research Park 97 Vincent Drive Birmingham B15 2SQ UK., Leach AG; Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester Manchester M13 9PL UK sam.butterworth@manchester.ac.uk., Jowitt TA; Wellcome Trust Centre for Cell Matrix Research, Faculty of Biology, Medicine and Health, University of Manchester Manchester M13 9PL UK., Qureshi O; Celentyx Ltd, Birmingham Research Park 97 Vincent Drive Birmingham B15 2SQ UK., Gordon J; Celentyx Ltd, Birmingham Research Park 97 Vincent Drive Birmingham B15 2SQ UK., Barnes NM; Celentyx Ltd, Birmingham Research Park 97 Vincent Drive Birmingham B15 2SQ UK.; Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham Edgbaston Birmingham B15 2TT UK., Brady CA; Celentyx Ltd, Birmingham Research Park 97 Vincent Drive Birmingham B15 2SQ UK.; Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham Edgbaston Birmingham B15 2TT UK., Raven EL; School of Chemistry, University of Bristol Cantock's Close Bristol BS8 1TS UK., Grainger RS; School of Chemistry, University of Birmingham Edgbaston Birmingham B15 2TT UK r.s.grainger@bham.ac.uk., Butterworth S; Division of Pharmacy and Optometry, Faculty of Biology, Medicine and Health, University of Manchester Manchester M13 9PL UK sam.butterworth@manchester.ac.uk.
Jazyk: angličtina
Zdroj: RSC chemical biology [RSC Chem Biol] 2021 Sep 13; Vol. 2 (6), pp. 1651-1660. Date of Electronic Publication: 2021 Sep 13 (Print Publication: 2021).
DOI: 10.1039/d0cb00209g
Abstrakt: The metabolism of l-tryptophan to N -formyl-l-kynurenine by indoleamine-2,3-dioxygenase 1 (IDO1) is thought to play a critical role in tumour-mediated immune suppression. Whilst there has been significant progress in elucidating the overall enzymatic mechanism of IDO1 and related enzymes, key aspects of the catalytic cycle remain poorly understood. Here we report the design, synthesis and biological evaluation of a series of tryptophan analogues which have the potential to intercept putative intermediates in the metabolism of 1 by IDO1. Functionally-relevant binding to IDO1 was demonstrated through enzymatic inhibition, however no IDO1-mediated metabolism of these compounds was observed. Subsequent T m -shift analysis shows the most active compound, 17, exhibits a distinct profile from known competitive IDO1 inhibitors, with docking studies supporting the hypothesis that 17 may bind at the recently-discovered S i site. These findings provide a start-point for development of further mechanistic probes and more potent tryptophan-based IDO1 inhibitors.
Competing Interests: NJC was a PhD student sponsored by Celentyx Ltd. TT, OQ, CAB are employees of Celentyx Ltd with share options in the company. JG and NMB are Directors of Celentyx Ltd with shareholdings in the company. There are no other conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
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