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

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.
Jinxin Che 1,  Feng Huang 1,  Mengmeng Zhang 2,  Gaoya Xu 2,  Bingxue Qu 1,  Jian Gao 1,  Binhui Chen 1,  Jianjun Zhang 3,  Huazhou Ying 1,  Yongzhou Hu 1,  Xiaobei Hu 2,  Yubo Zhou 2,  Anhui Gao 4,  Jia Li 5,  Xiaowu Dong 6
Affiliations

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 IDH2R140Q 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 IDH2R140Q 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.

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