Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase (TDO): design, synthesis and preclinical evaluation of novel TDO inhibitors
Eduard Dolusic1, Pierre Larrieu,2 Laurence Moineaux,1 Vincent Stroobant,2 Luc Pilotte,2 Didier Colau,2 Benoît Van den Eynde,2 Bernard Masereel,1 Johan Wouters,1 and Raphaël Frédérick1
1. Namur Drug Design and Discovery Center (ND3C), University of Namur, FUNDP, 61 Rue de Bruxelles, 5000 Namur, Belgium
2. Ludwig Institute for Cancer Research (LICR), Université Catholique de Louvain, 74 Avenue Hippocrate, 1200 Brussels, Belgium
Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development.
Recently, the team of Benoit Van den Eynde (LICR, UCL, Belgium) 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. In this communication, a detailed structure-activity study of a series of 3-(2-(pyridyl)ethenyl)indoles targeting TDO will be presented. This study led to the identification of a very potent, selective and orally available TDO inhibitor (LM10) which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors.
Our results thus describe a new mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.
|Title of host publication||Book of Abstracts, Emerging Targets and Treatments: Opportunities and Challenges for Drug Design, Ghent, 25 November 2011|
|Subtitle of host publication||Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (MedChem 2011)|
|Publication status||Published - 2011|
|Event||Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011) - Gand, Belgium|
Duration: 25 Nov 2011 → …
|Conference||Annual One-Day Meeting on Medicinal Chemistry of SRC & KVCV (Medchem 2011)|
|Period||25/11/11 → …|