2INInnovative drugs targeting IDO1 functions in neoplasia
| Publication Date: |
2018-03-06
|
|---|---|
| Publisher: |
Oxford University Press
|
| Print ISSN: |
0923-7534
|
| Electronic ISSN: |
1569-8041
|
| Topics: |
Medicine
|
| Published by: |
| _version_ | 1836398816175063040 |
|---|---|
| autor | Grohmann U, Macchiarulo A. |
| beschreibung | Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions. |
| citation_standardnr | 6178948 |
| datenlieferant | ipn_articles |
| feed_id | 19043 |
| feed_publisher | Oxford University Press |
| feed_publisher_url | http://global.oup.com/ |
| insertion_date | 2018-03-06 |
| journaleissn | 1569-8041 |
| journalissn | 0923-7534 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | Oxford University Press |
| quelle | Annals of Oncology |
| relation | https://academic.oup.com/annonc/article/doi/10.1093/annonc/mdy046.001/4917397?rss=1 |
| search_space | articles |
| shingle_author_1 | Grohmann U, Macchiarulo A. |
| shingle_author_2 | Grohmann U, Macchiarulo A. |
| shingle_author_3 | Grohmann U, Macchiarulo A. |
| shingle_author_4 | Grohmann U, Macchiarulo A. |
| shingle_catch_all_1 | 2INInnovative drugs targeting IDO1 functions in neoplasia Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions. Grohmann U, Macchiarulo A. Oxford University Press 0923-7534 09237534 1569-8041 15698041 |
| shingle_catch_all_2 | 2INInnovative drugs targeting IDO1 functions in neoplasia Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions. Grohmann U, Macchiarulo A. Oxford University Press 0923-7534 09237534 1569-8041 15698041 |
| shingle_catch_all_3 | 2INInnovative drugs targeting IDO1 functions in neoplasia Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions. Grohmann U, Macchiarulo A. Oxford University Press 0923-7534 09237534 1569-8041 15698041 |
| shingle_catch_all_4 | 2INInnovative drugs targeting IDO1 functions in neoplasia Background: Catabolism of amino acids is an ancient survival strategy that also controls immune responses in mammals. Indoleamine 2,3-dioxygenase 1 (IDO1), a tryptophan catabolizing enzyme, is recognized as an authentic regulator of immunity in several physiopathologic conditions, including neoplasia, in which it promotes immune unresponsiveness. However, IDO1 does not merely degrade tryptophan and produce immunoregulatory kynurenines but also acts as a signal-transducing molecule independently of its enzyme activity. IDO1’s signaling function relies on the presence of phosphorylable motifs in a region (small IDO1 domain) distant from the catalytic site (large IDO1 domain). Moreover, in the presence of the immunosuppressive cytokine TGF-β, the activation of the IDO1 signaling pathway has been shown to reprogram dendritic cells, the most professional antigen presenting cells, toward a stable and long term immunosuppressive phenotype that might possiby be relevant in the mechanisms of tumor immune escape. Although a potent and catalytic inhibitor of IDO1 is close to the market, being currently studied in a phase III trial in association with a checkpoint inhibitor, our data would suggest that in tumors dominated by high levels of TGF-β (such as colon cancers) IDO1 signaling rather than IDO1 catalytic activity coud be favoured. Therefore, drugs capable of inhibiting IDO1 signaling activity may be more effective in those contexts. Our hypothesis is that IDO1 exists in distinct conformations, associated with either catalytic or signaling activity, and that small compounds directly binding IDO1 may favor or unfavor the distinct conformations and thus IDO1's actions. Grohmann U, Macchiarulo A. Oxford University Press 0923-7534 09237534 1569-8041 15698041 |
| shingle_title_1 | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| shingle_title_2 | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| shingle_title_3 | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| shingle_title_4 | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| timestamp | 2025-06-30T23:33:05.200Z |
| titel | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| titel_suche | 2INInnovative drugs targeting IDO1 functions in neoplasia |
| topic | WW-YZ |
| uid | ipn_articles_6178948 |