IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer

Heng Liang; Tianqi Li; Xin Fang; Zikang Xing; Shengnan Zhang; Lei Shi; Weirui Li; Leilei Guo; Chunxiang Kuang; Hongrui Liu; Qing Yang

doi:10.1016/j.canlet.2021.09.012

IDO1/TDO dual inhibitor RY103 targets Kyn-AhR pathway and exhibits preclinical efficacy on pancreatic cancer

Cancer Lett. 2021 Dec 1:522:32-43. doi: 10.1016/j.canlet.2021.09.012. Epub 2021 Sep 11.

Authors

Heng Liang¹, Tianqi Li², Xin Fang³, Zikang Xing⁴, Shengnan Zhang⁵, Lei Shi⁶, Weirui Li⁷, Leilei Guo⁸, Chunxiang Kuang⁹, Hongrui Liu¹⁰, Qing Yang¹¹

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 19110700091@fudan.edu.cn.
² State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 16210700110@fudan.edu.cn.
³ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 18110700076@fudan.edu.cn.
⁴ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 17110700017@fudan.edu.cn.
⁵ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 17110700084@fudan.edu.cn.
⁶ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 18210700067@fudan.edu.cn.
⁷ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 17210700070@fudan.edu.cn.
⁸ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: 17210700113@fudan.edu.cn.
⁹ Shanghai Key Lab of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, Tongji University, Siping Road 1239, Shanghai, 200092, China. Electronic address: kuangcx@tongji.edu.cn.
¹⁰ Department of Pharmacology, School of Pharmacy, Fudan University, Zhangheng Road 826, Shanghai, 201203, China. Electronic address: liuhr@fudan.edu.cn.
¹¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Songhu Road 2005, Shanghai, 200438, China. Electronic address: yangqing68@fudan.edu.cn.

PMID: 34520819
DOI: 10.1016/j.canlet.2021.09.012

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzing the conversion of tryptophan (Trp) to kynurenine (Kyn) in kynurenine pathway (KP) is involved in the immunosuppression in pancreatic cancer (PC), but the value of IDO1 as an independent prognostic marker for PC is uncertain. Moreover, the correlation between tryptophan 2,3-dioxygenase (TDO), an isozyme of IDO1, and PC is largely unknown. Using TCGA database, the correlation between IDO1 and/or TDO expression and PC patients' survival was analyzed. The expressions of IDO1 and TDO in PC cells and PC mice were examined. The effects of IDO1, TDO or dual inhibition on IDO1 and TDO effector pathway (Aryl hydrocarbon receptor, AhR) and on migration and invasion of PC cells were investigated. The block effect of IDO1/TDO dual inhibitor RY103 on KP was evaluated. The preclinical efficacy of RY103 and its immunomodulatory effect on KPIC orthotopic PC mice and Pan02 tumor-bearing mice were explored. Results showed that IDO1/TDO co-expression is an independent prognostic marker for PC. RY103 can significantly block KP and target Kyn-AhR pathway to blunt the migration and invasion of PC cells, exhibit preclinical efficacy and ameliorate IDO1/TDO-mediated immunosuppression in PC mice.

Keywords: Kynurenine pathway; MDSCs; T cells; Tumor immunosuppression; Tumor metastasis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Movement / drug effects
Cell Proliferation / drug effects
Disease Models, Animal
Enzyme Inhibitors / pharmacology
Gene Expression Regulation, Neoplastic / drug effects
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics*
Kynurenine / biosynthesis
Mice
Neoplasm Invasiveness / genetics
Neoplasm Invasiveness / pathology
Organic Chemicals / pharmacology*
Organic Chemicals / therapeutic use
Pancreatic Neoplasms / drug therapy*
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / pathology
Receptors, Aryl Hydrocarbon / genetics*
Signal Transduction / drug effects
Tryptophan Oxygenase / antagonists & inhibitors
Tryptophan Oxygenase / genetics*

Substances

Enzyme Inhibitors
IDO1 protein, human
Indoleamine-Pyrrole 2,3,-Dioxygenase
Organic Chemicals
RY103
Receptors, Aryl Hydrocarbon
Kynurenine
Tryptophan Oxygenase