Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells

Jinxin Che; Feng Huang; Mengmeng Zhang; Gaoya Xu; Bingxue Qu; Jian Gao; Binhui Chen; Jianjun Zhang; Huazhou Ying; Yongzhou Hu; Xiaobei Hu; Yubo Zhou; Anhui Gao; Jia Li; Xiaowu Dong

doi:10.1016/j.ejmech.2020.112491

Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells

Eur J Med Chem. 2020 Oct 1:203:112491. doi: 10.1016/j.ejmech.2020.112491. Epub 2020 Jul 12.

Authors

Jinxin Che¹, Feng Huang¹, Mengmeng Zhang², Gaoya Xu², Bingxue Qu¹, Jian Gao¹, Binhui Chen¹, Jianjun Zhang³, Huazhou Ying¹, Yongzhou Hu¹, Xiaobei Hu², Yubo Zhou², Anhui Gao⁴, Jia Li⁵, Xiaowu Dong⁶

Affiliations

¹ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
² National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
³ Department of Pharmacy, The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, 310058, PR China.
⁴ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China. Electronic address: ahgao@simm.ac.cn.
⁵ National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; Open Studio for Druggability Research of Marine Natural Products, Pilot National Laboratory for Marine Science and Technology (Qingdao), 1 Wenhai Road, Aoshanwei, Jimo, Qingdao, 266237, PR China. Electronic address: jli@simm.ac.cn.
⁶ ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Hangzhou Institute of Innovative Medicine, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: dongxw@zju.edu.cn.

PMID: 32679449
DOI: 10.1016/j.ejmech.2020.112491

Abstract

The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2^R140Q inhibitory potency than AG-221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2^R140Q after computational docking and dynamic simulation, which may serve as a good starting point for further development.

Keywords: Conformational restriction; Inhibitors; Isocitrate dehydrogenase 2; Macrocyclic derivatives; Metabolic pathways.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Cell Line, Tumor
Chemistry Techniques, Synthetic
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / metabolism
Enzyme Inhibitors / pharmacology
Humans
Isocitrate Dehydrogenase / antagonists & inhibitors*
Isocitrate Dehydrogenase / chemistry
Isocitrate Dehydrogenase / genetics*
Isocitrate Dehydrogenase / metabolism
Leukemia, Myeloid, Acute / pathology*
Macrocyclic Compounds / chemical synthesis
Macrocyclic Compounds / chemistry*
Macrocyclic Compounds / metabolism
Macrocyclic Compounds / pharmacology*
Molecular Docking Simulation
Mutation*
Protein Conformation

Substances

Antineoplastic Agents
Enzyme Inhibitors
Macrocyclic Compounds
IDH2 protein, human
Isocitrate Dehydrogenase