2. Academic Validation
  3. Discovery, synthesis and biological evaluation of novel isoquinoline derivatives as potent indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase dual inhibitors

Discovery, synthesis and biological evaluation of novel isoquinoline derivatives as potent indoleamine 2, 3-dioxygenase 1 and tryptophan 2, 3-dioxygenase dual inhibitors

  • Eur J Med Chem. 2024 Sep 12:279:116852. doi: 10.1016/j.ejmech.2024.116852.
Zhiqian Lin 1,  Xiangli Ning 1,  Ruizhi Lai 1,  Li Hai 2,  Ruifang Nie 3,  Li Guo 1,  Guobo Li 1,  Zhongzhen Yang 4,  Yong Wu 5
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.
  • 2 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China; Central Nervous System Drug Key Laboratory of Sichuan Province, Luzhou, 646100, China.
  • 3 Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250000, China.
  • 4 Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, 610041, China. Electronic address: zhongzhenyang1991@wchscu.cn.
  • 5 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address: wyong@scu.edu.cn.
PMID: 39276584 DOI: 10.1016/j.ejmech.2024.116852
Abstract

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) play a pivotal role in regulating kynurenine catabolism pathway and immunosuppressive environment, which are promising drug targets for Cancer Immunotherapy. In this work, a variety of isoquinoline derivatives were designed, synthesized and evaluated for the inhibitory activity against IDO1 and TDO. The enzymatic assay and structure-activity relationship studies led to the most potent compound 43b with IC50 values of 0.31 μM for IDO1 and 0.08 μM for TDO, respectively. Surface plasmon resonance (SPR) revealed direct binding affinity of compound 43b to IDO1 and TDO and molecular docking studies were performed to predict the possible binding mode. Further pharmacokinetic study and biological evaluation in vivo showed that 43b displayed acceptable pharmacokinetic profiles and potent antitumor efficacy with low toxicity in B16-F10 tumor model, which might provide some insights into the discovery of novel IDO1/TDO inhibitors for Cancer Immunotherapy.

Keywords

Cancer therapy; Dual inhibitor; Indoleamine 2,3-dioxygenase; Isoquinoline; Tryptophan 2,3-dioxygenase.

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