Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 157, Issue -, Pages 423-436Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2018.08.013
Keywords
Indoleamine 2,3-dioxygenase 1; Cancer immunotherapy; Naphthoquinone derivatives; Tryptophan 2,3-dioxygenase
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Funding
- National Natural Science Foundation of China (NSFC) [81573272]
- Beijing Natural Science Foundation [7162109]
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Indoleamine 2,3-dioxygenase 1 (IDO1) mediated kynurenine pathway of tryptophan degradation is identified as an appealing and novel target in immunotherapy for the treatment of cancer. In this study, a novel series of naphthoquinone derivatives were synthesized, characterized and evaluated for their inhibitory activities against IDO1, and their structure-activity relationship was investigated. Among them, compounds T16, T44, T47, T49, T53 and T54 displayed potent IDO1 inhibitory activities with IC50 values ranging between 18 and 61 nM, which are more potent than INCB024360 undergoing clinical trial III evaluation. In addition, compounds T28, T44 and T53 decreased the kynurenine levels in rat plasma by 30%-50%. Compounds exhibiting excellent IDO1 inhibitory activities were also evaluated for their inhibitory activities against tryptophan 2,3-dioxygenase (TDO). Of which, compound T28 (IDO1 IC50 = 120 nM) showed promising TDO inhibition (1050 72 nM) and was identified as an IDO1/TDO dual inhibitor. (C) 2018 Elsevier Masson SAS. All rights reserved.
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