Discovery of Icotinib-1,2,3-Triazole Derivatives as IDO1 Inhibitors.

Long-Fei Mao,Xiao-Jun Yao,Jie Zhao,Gui-Qing Xu,Yue-Ming Li,Yu-Wei Wang

doi:10.3389/fphar.2020.579024

Abstract

Tumor immunotherapy is considered to be a highlight in cancer treatment in recent years. Indoleamine 2,3-dioxygenase 1 (IDO1) is closely related to the over expression of many cancers, and is therefore a promising target for tumor immunotherapy. To search for novel IDO1-targeting therapeutic agents, 22 icotinib-linked 1,2,3-triazole derivatives were prepared and evaluated for their inhibitory activity against IDO1. The structures of the prepared compounds were confirmed with1H NMR, 13C NMR and HR MS. IDO1 inhibitory activity assay results indicated that 10 of those compounds showed remarkable inhibitory activity against IDO1, among which compound a17 was the most potent with IC50value of 0.37 μM. The binding model between the prepared compounds and IDO1 was studied with molecular modeling study. The current study suggested that icotinib-1,2,3-triazole derivatives could be used as potential inhibitors that preferentially bind to the ferrous form of IDO1 through the formation of coordinate bond with the haem iron.

Highlights

Tumor immunotherapy is an emerging field in tumor treatment
To investigate the IDO1 inhibition activities of the synthesized derivatives, all the new compounds and icotinib were screened via Hela cell-based functional assay using methods described in the literature (Yue et al, 2009; Malachowski et al, 2016; Qian et al, 2016)
BMS-986205 was used as a positive control and the IC50 value was tested as 0.62 nM, which is consistent with the results previously reported by Nelp et al (IC50 = 0.5 nM) (Nelp et al, 2018)

Summary

Introduction

Studies show that indoleamine 2,3dioxygenase 1 (IDO1) is the initial and rate-limiting enzyme that catalyzes the metabolism of tryptophan along the kynurenine pathway outside the human liver (Chen et al, 2019), and plays an important role in regulating the body’s innate and adaptive immunity by catalyzing tryptophan metabolism (Takikawa et al, 1986; Takikawa, 2005). Tumor cells can induce IDO1 over expression, which causes the depletion of local tryptophan and the accumulation of metabolites such as kynurenine, thereby activating GCN2 and AHR signaling pathways, inhibiting T cell proliferation, and inducing apoptosis (Muller et al, 2005). Over expression of IDO1 has been found in a variety of malignant tumors, such as ovarian cancer, pancreatic cancer, and non-small cell lung cancer. IDO1 inhibitors once attracted considerable attention as potential agents for cancer treatment

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Conclusion