Bifunctional Naphthoquinone Aromatic Amide-Oxime Derivatives Exert Combined Immunotherapeutic and Antitumor Effects through Simultaneous Targeting of Indoleamine-2,3-dioxygenase and Signal Transducer and Activator of Transcription 3
| Autor: | Ying-Ming Pan, Jing Xiaoteng, Zhen-Feng Chen, Ri-Zhen Huang, Ye Zhang, Gui-Bin Liang, Yi-Lin Fang, Heng-Shan Wang, Xiaochao Huang, Zhi-Xin Liao |
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| Rok vydání: | 2020 |
| Předmět: |
STAT3 Transcription Factor
Mice Nude Antineoplastic Agents 01 natural sciences 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship In vivo Cell Line Tumor Drug Discovery Oximes medicine Structure–activity relationship Animals Humans Immunologic Factors Indoleamine-Pyrrole 2 3 -Dioxygenase Doxorubicin Enzyme Inhibitors STAT3 Indoleamine 2 3-dioxygenase 030304 developmental biology 0303 health sciences Tumor microenvironment biology Molecular Structure Chemistry Xenograft Model Antitumor Assays Naphthoquinone 0104 chemical sciences Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry STAT protein biology.protein Cancer research Molecular Medicine Tumor Escape Drug Screening Assays Antitumor medicine.drug Naphthoquinones |
| Zdroj: | Journal of medicinal chemistry. 63(4) |
| ISSN: | 1520-4804 |
| Popis: | Indoleamine-2,3-dioxygenase 1 (IDO1) and signal transducer and activator of transcription 3 (STAT3) are important targets in the tumor microenvironment for cancer therapy. In the present study, a set of naphthoquinone aromatic amide-oxime derivatives were designed, which stimulated the immune response via IDO1 inhibition and simultaneously displayed powerful antitumor activity against three selected cancer cell lines through suppressing STAT3 signaling. The representative compound 8u bound effectively to IDO1, with greater inhibitory activity relative to the commercial IDO1 inhibitor 4-amino-N-(3-chloro-4-fluorophenyl)-N'-hydroxy-1,2,5-oxadiazole-3-carboximidamide (IDO5L) in addition to the efficient suppression of nuclear translocation of STAT3. Consistently, in vivo assays demonstrated a higher antiproliferative activity of compound 8u in both wild-type B16-F10 isograft tumors and an athymic HepG2 xenograft model relative to 1-methyl-l-tryptophan (1-MT) and doxorubicin (DOX). This bifunctional compound with dual immunotherapeutic and anticancer efficacy may represent a new generation of highly efficacious drug candidates for cancer therapy. |
| Databáze: | OpenAIRE |
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