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Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators

Tryptophan 2,3-dioxygenase (TDO) inhibitors. 3-(2-(pyridyl)ethenyl)indoles as potential anticancer immunomodulators

Authors :
Pierre Larrieu
Eduard Dolusic
Laurence Moineaux
Lionel Pochet
Luc Pilotte
Raphaël Frédérick
Bernard Masereel
Johan Wouters
Benoît Van den Eynde
Vincent Stroobant
Didier Colau
Source :
Journal of Medicinal Chemistry. 54(15):5320-5334
Publication Year :
2011
Publisher :
American Chemical Society, 2011.

Abstract

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance. IDO inhibition is thus an active area of research in drug development. Recently, our group has shown that tryptophan 2,3-dioxygenase (TDO), an unrelated hepatic enzyme also catalyzing the first step of tryptophan degradation, is also expressed in many tumors and that this expression prevents tumor rejection by locally depleting tryptophan. Herein, we report a structure-activity study on a series of 3-(2-(pyridyl)ethenyl)indoles. More than 70 novel derivatives were synthesized, and their TDO inhibitory potency was evaluated. The rationalization of the structure-activity relationships (SARs) revealed essential features to attain high TDO inhibition and notably a dense H-bond network mainly involving His(55) and Thr(254) residues. Our study led to the identification of a very promising compound (58) displaying good TDO inhibition (K(i) = 5.5 μM), high selectivity, and good oral bioavailability. Indeed, 58 was chosen for preclinical evaluation.

Details

Language :
English
ISSN :
00222623
Volume :
54
Issue :
15
Database :
OpenAIRE
Journal :
Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....2e6a2bcd6407d829fe9ec4a24a0b478e
Full Text :
https://doi.org/10.1021/jm2006782