Identification of selective inhibitors of indoleamine 2,3-dioxygenase 2.

Abstract

The kynurenine pathway is responsible for the breakdown of the majority of the essential amino acid, tryptophan (Trp). The first and rate-limiting step of the kynurenine pathway can be independently catalysed by tryptophan 2,3-dioxygenase (Tdo2), indoleamine 2,3-dioxygenase 1 (Ido1) or indoleamine 2,3-dioxygenase 2 (Ido2). Tdo2 or Ido1 enzymatic activity has been implicated in a number of actions of the kynurenine pathway, including immune evasion by tumors. IDO2 is expressed in several human pancreatic cancer cell lines, suggesting it also may play a role in tumorigenesis. Although Ido2 was originally suggested to be a target of the chemotherapeutic agent dextro-1-methyl-tryptophan, subsequent studies suggest this compound does not inhibit Ido2 activity. The development of selective Ido2 inhibitors could provide valuable tools for investigating its activity in tumor development and normal physiology. In this study, a library of Food and Drug Administration-approved drugs was screened for inhibition of mouse Ido2 enzymatic activity. A number of candidates were identified and IC(50) values of each compound for Ido1 and Ido2 were estimated. The Ido2 inhibitors were also tested for inhibition of Tdo2 activity. Our results showed that compounds from a class of drugs used to inhibit proton pumps were the most potent and selective Ido2 inhibitors identified in the library screen. These included tenatoprazole, which exhibited an IC(50) value of 1.8μM for Ido2 with no inhibition of Ido1 or Tdo2 activity detected at a concentration of 100μM tenatoprazole. These highly-selective Ido2 inhibitors will be useful for defining the distinct biological roles of the three Trp-catabolizing enzymes.

• Authors: Supun M Bakmiwewa, Amos A Fatokun, Anh Tran, Richard J Payne, Nicholas H Hunt, Helen J Ball
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 22 Issue 24 Pg. 7641-6 (Dec 15 2012) ISSN: 1464-3405 [Electronic] England
• PMID: 23122865 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 Elsevier Ltd. All rights reserved.

Chemical References

• Enzyme Inhibitors
• Indoleamine-Pyrrole 2,3,-Dioxygenase

Topics

• Animals
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (chemistry, pharmacology)
• HEK293 Cells
• Humans
• Indoleamine-Pyrrole 2,3,-Dioxygenase (antagonists & inhibitors, metabolism)
• Mice
• Models, Molecular
• Molecular Structure
• Structure-Activity Relationship
• Substrate Specificity