2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors

Design, Synthesis, and Biological Evaluation of Novel Hydroxyamidine Derivatives as Indoleamine 2,3-Dioxygenase 1 Inhibitors

  • ACS Med Chem Lett. 2025 Jun 30;16(7):1401-1409. doi: 10.1021/acsmedchemlett.5c00279.
Xiaodan Qiu 1,  Yitong Liu 1,  Xia Zhou 1 2,  Cong Zhao 1 3,  Qingguo Meng 2,  Wuli Zhao 1 3,  Guangzhi Shan 1
Affiliations

Affiliations

  • 1 Institute of Medicinal Biotechnology, Peking Union Medical College & Chinese Academy of Medical Sciences, Tian Tan Xi Li No.1, Beijing 100050, PR China.
  • 2 School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System & Biotech Drugs in Universities of Shandong, Key Laboratory of Molecular Pharmacology & Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, PR China.
  • 3 State Key Laboratory of Respiratory Health and Multimorbidity, Key Laboratory of Antibiotic Bioengineering, Ministry of Health, Laboratory of Oncology, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, PR China.
PMID: 40666486 DOI: 10.1021/acsmedchemlett.5c00279
Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) is a rate-limiting enzyme that catalyzes the conversion of tryptophan into kynurenine and represents a potential target for tumor immunotherapy. In this study, we designed and synthesized a series of N'-hydroxyamidine analogues through pharmacophore fusion and bioisosterism principles. The results indicated that compounds I-1 and I-2 exhibited activity similar to that of Epacadostat in inhibiting recombinant hIDO1 and hIDO1 expression in HeLa cells. Moreover, the compounds not only effectively stimulated T cell proliferation but also inhibited the proliferation of Lewis Lung Carcinoma cells. RNA Sequencing analysis indicated that these compounds primarily exert immunotherapeutic effects. Surface plasmon resonance and molecular docking confirmed the interactions between the compounds and IDO1. The physicochemical properties along with pharmacokinetic profiles of both compounds were also predicted, and they were found to possess favorable characteristics. The active compounds developed in this research may serve as valuable references for discovering highly effective IDO1 inhibitors.

Keywords

IDO1; hydroxyamidine derivatives; tumor immunotherapy.

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