Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy

Eduard Dolusic, Sébastien Blanc, Pierre Larrieu, Laurence Moineaux, Delphine Colette, Graeme Fraser, Vincent Stroobant, Luc Pilotte, Didier Colau, Johan Wouters, Bernard Masereel, Benoît Van den Eynde, Raphaël Frédérick

Research output: Contribution to conferencePoster

18 Downloads (Pure)

Abstract

Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumors to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumors express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. [1] The recent elucidation of the three-dimensional structures of IDO[2], in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of analogues as well as a modeling study explaining the SAR will be presented. [3]
Original languageEnglish
PagesBook of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23-27, 2010
Number of pages1
Publication statusPublished - 2010
EventXXIVth European Colloquium on Heterocyclic Chemistry - Vienna, Austria
Duration: 23 Aug 201027 Aug 2010

Conference

ConferenceXXIVth European Colloquium on Heterocyclic Chemistry
CountryAustria
CityVienna
Period23/08/1027/08/10

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Immunotherapy
Neoplasms
Tryptophan
Drug Design
Cyanides
Drug Discovery
Immunosuppressive Agents
indole
Inhibitory Concentration 50
Immune System
Vaccination
Cell Proliferation
Ions
T-Lymphocytes
Enzymes
Therapeutics

Cite this

Dolusic, E., Blanc, S., Larrieu, P., Moineaux, L., Colette, D., Fraser, G., ... Frédérick, R. (2010). Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy. Book of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23-27, 2010. Poster session presented at XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria.
Dolusic, Eduard ; Blanc, Sébastien ; Larrieu, Pierre ; Moineaux, Laurence ; Colette, Delphine ; Fraser, Graeme ; Stroobant, Vincent ; Pilotte, Luc ; Colau, Didier ; Wouters, Johan ; Masereel, Bernard ; Van den Eynde, Benoît ; Frédérick, Raphaël. / Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy. Poster session presented at XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria.1 p.
@conference{5c59940f9e654690a42825bd28fd2b8f,
title = "Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy",
abstract = "Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumors to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumors express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. [1] The recent elucidation of the three-dimensional structures of IDO[2], in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of analogues as well as a modeling study explaining the SAR will be presented. [3]",
author = "Eduard Dolusic and S{\'e}bastien Blanc and Pierre Larrieu and Laurence Moineaux and Delphine Colette and Graeme Fraser and Vincent Stroobant and Luc Pilotte and Didier Colau and Johan Wouters and Bernard Masereel and {Van den Eynde}, Beno{\^i}t and Rapha{\"e}l Fr{\'e}d{\'e}rick",
year = "2010",
language = "English",
pages = "Book of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23--27, 2010",
note = "XXIVth European Colloquium on Heterocyclic Chemistry ; Conference date: 23-08-2010 Through 27-08-2010",

}

Dolusic, E, Blanc, S, Larrieu, P, Moineaux, L, Colette, D, Fraser, G, Stroobant, V, Pilotte, L, Colau, D, Wouters, J, Masereel, B, Van den Eynde, B & Frédérick, R 2010, 'Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy', XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, 23/08/10 - 27/08/10 pp. Book of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23-27, 2010.

Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy. / Dolusic, Eduard; Blanc, Sébastien; Larrieu, Pierre; Moineaux, Laurence; Colette, Delphine; Fraser, Graeme; Stroobant, Vincent; Pilotte, Luc; Colau, Didier; Wouters, Johan; Masereel, Bernard; Van den Eynde, Benoît; Frédérick, Raphaël.

2010. Book of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23-27, 2010 Poster session presented at XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria.

Research output: Contribution to conferencePoster

TY - CONF

T1 - Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy

AU - Dolusic, Eduard

AU - Blanc, Sébastien

AU - Larrieu, Pierre

AU - Moineaux, Laurence

AU - Colette, Delphine

AU - Fraser, Graeme

AU - Stroobant, Vincent

AU - Pilotte, Luc

AU - Colau, Didier

AU - Wouters, Johan

AU - Masereel, Bernard

AU - Van den Eynde, Benoît

AU - Frédérick, Raphaël

PY - 2010

Y1 - 2010

N2 - Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumors to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumors express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. [1] The recent elucidation of the three-dimensional structures of IDO[2], in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of analogues as well as a modeling study explaining the SAR will be presented. [3]

AB - Immunotherapy is a promising novel and validated strategy for cancer therapy. It consists of the therapeutic vaccination of patients to stimulate their (natural) immune system against cancer cells. However, this approach showed a limited efficacy in vivo because cancer cells develop enzymatic mechanisms allowing tumors to resist or escape immune rejection. Among the enzymes involved, indoleamine 2,3-dioxygenase (IDO) was identified as a potential actor. IDO catalyses the rapid degradation of tryptophan (Trp) into N-formylkynurenine. This results in a local Trp depletion that severely affects T-cells proliferation and is thereby deeply immunosuppressive. Recently, the team of Prof. Van den Eynde demonstrated that many human tumors express IDO in a constitutive manner and that this expression allows cancer cells to escape immune rejection. IDO was thus clearly identified as an attractive target for the development of inhibitors. [1] The recent elucidation of the three-dimensional structures of IDO[2], in complex with phenylimidazole and the cyanide ion (CN¯), provide important results for the structure-based drug discovery and design of novel IDO inhibitors. In the present work, we applied virtual screening for the discovery of new IDO inhibitors. As a result, five novel scaffolds with inhibitory potencies in the micromolar range were identified. Among these, the most promising candidate (1: IC50 = 65 µM) was selected and its inhibitory potency improved by chemical modifications. This led to a 7-fold improvement of the inhibitory potency of the hit selected. In this communication, the identification of 1, the synthesis and biological evaluation of analogues as well as a modeling study explaining the SAR will be presented. [3]

M3 - Poster

SP - Book of Abstracts, XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria, August 23-27, 2010

ER -

Dolusic E, Blanc S, Larrieu P, Moineaux L, Colette D, Fraser G et al. Indole-pyridinyl-ethanones as Novel Inhibitors of Indoleamine 2,3-Dioxygenase (IDO), a Promising Target forAnti-Cancer Immunotherapy. 2010. Poster session presented at XXIVth European Colloquium on Heterocyclic Chemistry, Vienna, Austria.