4,5-Disubstituted 1,2,3-triazoles: Effective Inhibition of Indoleamine 2,3-Dioxygenase 1 Enzyme Regulates T cell Activity and Mitigates Tumor Growth.
Animals
Antineoplastic Agents, Immunological
/ chemistry
Breast Neoplasms
/ drug therapy
Carcinoma, Ehrlich Tumor
/ drug therapy
Cell Line, Tumor
Drug Screening Assays, Antitumor
Enzyme Assays
Female
HEK293 Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase
/ antagonists & inhibitors
Inhibitory Concentration 50
Kynurenine
/ immunology
Metabolic Networks and Pathways
/ drug effects
Mice
Molecular Docking Simulation
Primary Cell Culture
Recombinant Proteins
/ chemistry
T-Lymphocytes, Cytotoxic
/ drug effects
Triazoles
/ chemistry
Tryptophan
/ immunology
Tryptophan Oxygenase
/ antagonists & inhibitors
Tumor Escape
/ drug effects
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
05 12 2019
05 12 2019
Historique:
received:
31
05
2019
accepted:
21
11
2019
entrez:
6
12
2019
pubmed:
6
12
2019
medline:
12
11
2020
Statut:
epublish
Résumé
The improvement of body's own immune system is considered one of the safest approaches to fight against cancer and several other diseases. Excessive catabolism of the essential amino acid, L-tryptophan (L-Trp) assists the cancer cells to escape normal immune obliteration. The formation of disproportionate kynurenine and other downstream metabolites suppress the T cell functions. Blocking of this immunosuppressive mechanism is considered as a promising approach against cancer, neurological disorders, autoimmunity, and other immune-mediated diseases. Overexpression of indoleamine 2,3-dioxygenase 1 (IDO1) enzyme is directly related to the induction of immunosuppressive mechanisms and represents an important therapeutic target. Several classes of small molecule-based IDO1 inhibitors have been already reported, but only few compounds are currently being evaluated in various stages of clinical trials as adjuvants or in combination with chemo- and radiotherapies. In the quest for novel structural class(s) of IDO1 inhibitors, we developed a series of 4,5-disubstituted 1,2,3-triazole derivatives. The optimization of 4,5-disubstituted 1,2,3-triazole scaffold and comprehensive biochemical and biophysical studies led to the identification of compounds, 3i, 4i, and 4k as potent and selective inhibitors of IDO1 enzyme with IC
Identifiants
pubmed: 31804586
doi: 10.1038/s41598-019-54963-9
pii: 10.1038/s41598-019-54963-9
pmc: PMC6895048
doi:
Substances chimiques
Antineoplastic Agents, Immunological
0
IDO1 protein, human
0
IDO1 protein, mouse
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Recombinant Proteins
0
Triazoles
0
Kynurenine
343-65-7
Tryptophan
8DUH1N11BX
Tryptophan Oxygenase
EC 1.13.11.11
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
18455Références
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