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  4. Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors
 
research article

Detailed analysis and follow-up studies of a high-throughput screening for indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors

Roehrig, Ute F.
•
Majjigapu, Somi Reddy  
•
Chambon, Marc  
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2014
European Journal Of Medicinal Chemistry

Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulator of immune responses and therefore an important therapeutic target for the treatment of diseases that involve pathological immune escape, such as cancer. Here, we describe a robust and sensitive high-throughput screen (HTS) for IDO1 inhibitors using the Prestwick Chemical Library of 1200 FDA-approved drugs and the Maybridge HitFinder Collection of 14,000 small molecules. Of the 60 hits selected for follow-up studies, 14 displayed IC50 values below 20 mu M under the secondary assay conditions, and 4 showed an activity in cellular tests. In view of the high attrition rate we used both experimental and computational techniques to identify and to characterize compounds inhibiting IDO1 through unspecific inhibition mechanisms such as chemical reactivity, redox cycling, or aggregation. One specific IDO1 inhibitor scaffold, the imidazole antifungal agents, was chosen for rational structure-based lead optimization, which led to more soluble and smaller compounds with micromolar activity. (C) 2014 Elsevier Masson SAS. All rights reserved.

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Type
research article
DOI
10.1016/j.ejmech.2014.06.078
Web of Science ID

WOS:000341464500028

Author(s)
Roehrig, Ute F.
Majjigapu, Somi Reddy  
Chambon, Marc  

EPFL

Bron, Sylvian
Pilotte, Luc
Colau, Didier
Van Den Eynde, Benoit J.
Turcatti, Gerardo  

EPFL

Vogel, Pierre  
Zoete, Vincent
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Date Issued

2014

Publisher

Elsevier France-Editions Scientifiques Medicales Elsevier

Published in
European Journal Of Medicinal Chemistry
Volume

84

Start page

284

End page

301

Subjects

Cancer immunotherapy

•

Enzyme inhibition

•

High throughput screening

•

Indoleamine 2,3-dioxygenase

•

In silico drug design

•

Molecular dynamics simulations

•

Structure-activity relationship

•

Tryptophan metabolism

Editorial or Peer reviewed

REVIEWED

Written at

EPFL

EPFL units
LGSA  
PTCB  
Available on Infoscience
October 23, 2014
Use this identifier to reference this record
https://infoscience.epfl.ch/handle/20.500.14299/107666
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