Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction

Xuechen Zhou; Mengzhu Zheng; Na Zhao; Yixin Hu; Kaiyin Yang; Junfeng Huo; Guangyuan Liu; Jiangeng Huang; Lixia Chen; Yirong Zhou; Hua Li

doi:10.1016/j.bioorg.2021.105569

Discovery of linear unnatural peptides as potent mutant isocitrate dehydrogenase 1 inhibitors by Ugi reaction

Bioorg Chem. 2022 Feb:119:105569. doi: 10.1016/j.bioorg.2021.105569. Epub 2021 Dec 20.

Authors

Xuechen Zhou¹, Mengzhu Zheng¹, Na Zhao², Yixin Hu¹, Kaiyin Yang¹, Junfeng Huo¹, Guangyuan Liu¹, Jiangeng Huang³, Lixia Chen⁴, Yirong Zhou⁵, Hua Li⁶

Affiliations

¹ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Key Laboratory of Xinjiang Phytomedicine Resource and Utilization, Ministry of Education, School of Pharmacy, Shihezi University, Shihezi 832002, China.
³ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: jiangenghuang@hust.edu.cn.
⁴ Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: syzyclx@163.com.
⁵ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: zhouyirong@hust.edu.cn.
⁶ Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Tongji-Rongcheng Center for Biomedicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; Wuya College of Innovation, Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: li_hua@hust.edu.cn.

PMID: 34954572
DOI: 10.1016/j.bioorg.2021.105569

Abstract

Isocitrate dehydrogenases 1 (IDH1) catalyzes the oxidative decarboxylation of isocitrate to ɑ-ketoglutaric acid (α-KG). It is the most frequently mutated metabolic gene in human cancer and its mutations interfere with cell metabolism and epigenetic regulation, thus promoting tumorigenesis. In order to discover potent new mutant IDH1 inhibitors, based on the structure of marketed inhibitor AG-120 (Ivosidenib), we designed, synthesized and evaluated a series of linear unnatural peptide analogues via Ugi reaction, as potential mutant IDH1 inhibitors. All these compounds were evaluated for their inhibition on mutant IDH1 enzyme activity. The structure-activity relationship was discussed on the basis of experimental data, with an attempt to pave the way for future studies. Among them, 43 exhibited potent and selective enzyme inhibitory activity, and showed strong binding affinity with mutant IDH1. It can decrease the cellular concentration of 2-HG, and suppress the proliferation of HT1080 and IDH1 mutant-U-87 cells by selectively inhibiting the activity of mutant IDH1.

Keywords: Antitumor; Inhibition of 2-HG production; Mutant IDH1; Ugi reaction.

Publication types

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

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery*
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Isocitrate Dehydrogenase / antagonists & inhibitors*
Isocitrate Dehydrogenase / genetics
Isocitrate Dehydrogenase / metabolism
Molecular Structure
Mutation
Peptides / chemical synthesis
Peptides / chemistry
Peptides / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Enzyme Inhibitors
Peptides
Isocitrate Dehydrogenase
IDH1 protein, human