2. Academic Validation
  3. Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation

Discovery of 2-substituted-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxamide as potent and selective protein arginine methyltransferases 5 inhibitors: Design, synthesis and biological evaluation

  • Eur J Med Chem. 2019 Feb 15:164:317-333. doi: 10.1016/j.ejmech.2018.12.065.
Jingwei Shao 1,  Kongkai Zhu 2,  Daohai Du 3,  Yuanyuan Zhang 3,  Hongrui Tao 4,  Zhifeng Chen 3,  Hualiang Jiang 3,  Kaixian Chen 5,  Cheng Luo 6,  Wenhu Duan 7
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China.
  • 2 School of Biological Science and Technology, University of Jinan, Jinan, 250022, PR China.
  • 3 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 4 School of Biological Science and Technology, University of Jinan, Jinan, 250022, PR China; Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China.
  • 5 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Open Studio for Drugability Research of Marine Natural Products, Qingdao National Laboratory for Marine Science and Technology, Wenhai Road, Aoshanwei, Jimo, Qingdao, Shangdong, 266237, China.
  • 6 Drug Discovery and Design Center, CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai, 201203, China; Open Studio for Drugability Research of Marine Natural Products, Qingdao National Laboratory for Marine Science and Technology, Wenhai Road, Aoshanwei, Jimo, Qingdao, Shangdong, 266237, China. Electronic address: cluo@simm.ac.cn.
  • 7 Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (CAS), Shanghai, 201203, China. Electronic address: whduan@simm.ac.cn.
PMID: 30605830 DOI: 10.1016/j.ejmech.2018.12.065
Abstract

Protein arginine methyltransferases 5 (PRMT5) represents an attractive drug target in epigenetic field for the treatment of leukemia and lymphoma. Here, a series of N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)amide derivatives targeting PRMT5 were designed with structure-based approach and synthesized. Among them, compound 46 showed potent and selective PRMT5 inhibition activity with an IC50 of 8.5 nM, which was approximately equivalent with the phase I clinical trial PRMT5 Inhibitor GSK-3326595 (IC50 = 5.5 nM). Compound 46 also displayed pronounced anti-proliferative activity in MV4-11 cells (GI50 = 18 nM) and antitumor activity in MV4-11 mouse xenografts model. This molecule can serve as an excellent tool compound for probing the biological function of PRMT5.

Keywords

Anti-tumor; N-Substituted 1,2,3,4-tetrahydroisoquinoline derivatives; PRMT5 inhibitors.

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