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. Epub 2018 Dec 26.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Drug Discovery*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Heterografts
  • Humans
  • Mice
  • Protein-Arginine N-Methyltransferases / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / chemistry
  • Tetrahydroisoquinolines / pharmacology*

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Tetrahydroisoquinolines
  • PRMT5 protein, human
  • Protein-Arginine N-Methyltransferases