Discovery of secondary sulphonamides as IDO1 inhibitors with potent antitumour effects in vivo
| Autor: | Haiqing Zhong, Yue Hu, Yi Zou, Wang Fang, Yisheng Lai, Yan Wang, Li Yuezhen, Wenjie Guo, Ge Shushan, Qiang Xu, Zheng Yingbo, Wen Liu, Xuewei Ma |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Spectrometry Mass Electrospray Ionization Kynurenine pathway Protein Conformation Proton Magnetic Resonance Spectroscopy T-Lymphocytes Antineoplastic Agents Apoptosis RM1-950 Crystallography X-Ray 01 natural sciences Mice In vivo Drug Discovery Animals Humans Indoleamine-Pyrrole 2 3 -Dioxygenase Indoleamine 2 3-dioxygenase 1 Enzyme Inhibitors immune checkpoint Cell Proliferation Pharmacology chemistry.chemical_classification Mice Inbred BALB C Sulfonamides 010405 organic chemistry Chemistry Immune escape immune escape Cell Differentiation General Medicine Tryptophan Metabolism Immune checkpoint 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme secondary sulphonamides Biochemistry Therapeutics. Pharmacology Research Paper kynurenine pathway HeLa Cells |
| Zdroj: | Journal of Enzyme Inhibition and Medicinal Chemistry Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1240-1257 (2020) |
| ISSN: | 1475-6374 1475-6366 |
| Popis: | Indoleamine 2,3-dioxygenase 1 (IDO1) as a key rate-limiting enzyme in the kynurenine pathway of tryptophan metabolism plays an important role in tumour immune escape. Herein, a variety of secondary sulphonamides were synthesised and evaluated in the HeLa cell-based IDO1/kynurenine assay, leading to the identification of new IDO1 inhibitors. Among them, compounds 5d, 5l and 8g exhibited the strongest inhibitory effect with significantly improved activity over the hit compound BS-1. The in vitro results showed that these compounds could restore the T cell proliferation and inhibit the differentiation of naïve CD4+ T cell into highly immunosuppressive FoxP3+ regulatory T (Treg) cell without affecting the viability of HeLa cells and the expression of IDO1 protein. Importantly, the pharmacodynamic assay showed that compound 5d possessed potent antitumour effect in both CT26 and B16F1 tumours bearing immunocompetent mice but not in immunodeficient mice. Functionally, subsequent experiments demonstrated that compound 5d could effectively inhibit tumour cell proliferation, induce apoptosis, up-regulate the expression of IFN-γ and granzyme B, and suppress FoxP3+ Treg cell differentiation, thereby activate the immune system. Thus, compound 5d could be a potential and efficacious agent for further evaluation. |
| Databáze: | OpenAIRE |
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