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In this study, we synthesized three novel 2-amino-1,4-naphthoquinone amide-oxime derivatives and identified them as dual inhibitors of IDO1 and STAT3. The representative compound NK3 demonstrated effective binding to IDO1 and exhibited good inhibitory activity (hIDO1 IC50 = 0.06 \u03bcM), leading to its selection for further investigation. The direct interactions between compound NK3 and IDO1 and STAT3 proteins were confirmed through surface plasmon resonance analysis. A molecular docking study of compound NK3 revealed key interactions between NK3 and IDO1, with the naphthoquinone-oxime moiety coordinating with the heme iron. In the in vitro anticancer assay, compound NK3 displayed potent antitumor activity against selected cancer cell lines and effectively suppressed nuclear translocation of STAT3. Moreover, in vivo assays conducted on CT26 tumor-bearing Balb\/c mice and an athymic HepG2 xenograft model revealed that compound NK3 exhibited potent antitumor activity with low toxicity relative to 1-methyl-L-tryptophan (1-MT) and doxorubicin (DOX). Overall, these findings provided evidence that the dual inhibitors of IDO1 and STAT3 may offer a promising avenue for the development of highly effective drug candidates for cancer therapy.<\/jats:p>","DOI":"10.3390\/molecules28166135","type":"journal-article","created":{"date-parts":[[2023,8,21]],"date-time":"2023-08-21T01:46:56Z","timestamp":1692582416000},"page":"6135","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Synthesis and Biological Evaluation of Novel 2-Amino-1,4-Naphthoquinone Amide-Oxime Derivatives as Potent IDO1\/STAT3 Dual Inhibitors with Prospective Antitumor Effects"],"prefix":"10.3390","volume":"28","author":[{"given":"Ri-Zhen","family":"Huang","sequence":"first","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiao-Ling","family":"Liang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Teng","family":"Jing","sequence":"additional","affiliation":[{"name":"State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China"},{"name":"Department of Chemistry & Pharmaceutical Science, Guilin Normal College, Xinyi Road 15, Guilin 541001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Wang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui-Yong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng-Shan","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory for the Chemistry and Molecular Engineering of Medicinal Resources, Collaborative Innovation Center for Guangxi Ethnic Medicine, School of Chemistry and Pharmaceutical Sciences of Guangxi Normal University, Guilin 541004, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Li","family":"Ma","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Hua","family":"Wei","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Guangxi Key Laboratory of Drug Discovery and Optimization, Guangxi Engineering Research Center for Pharmaceutical Molecular Screening and Druggability Evaluation, School of Pharmacy, Guilin Medical University, Guilin 541199, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1126\/science.aaa8172","article-title":"The future of immune checkpoint therapy","volume":"348","author":"Sharma","year":"2015","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3335","DOI":"10.1172\/JCI83871","article-title":"Cancer immunotherapy: Harnessing the immune system to battle cancer","volume":"125","author":"Yang","year":"2015","journal-title":"J. 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