Structure-based modification of pyrazolone derivatives to inhibit mTORC1 by targeting the leucyl-tRNA synthetase-RagD interaction

Bioorg Chem. 2021 Jul:112:104907. doi: 10.1016/j.bioorg.2021.104907. Epub 2021 Apr 20.

Abstract

The enzyme leucyl-tRNA synthetase (LRS) and the amino acid leucine regulate the mechanistic target of rapamycin (mTOR) signaling pathway. Leucine-dependent mTORC1 activation depends on GTPase activating protein events mediated by LRS. In a prior study, compound BC-LI-0186 was discovered and shown to interfere with the mTORC1 signaling pathway by inhibiting the LRS-RagD interaction. However, BC-LI-0186 exhibited poor solubility and was metabolized by human liver microsomes. In this study, in silico physicochemical properties and metabolite analysis of BC-LI-0186 are used to investigate the addition of functional groups to improve solubility and microsomal stability. In vitro experiments demonstrated that 7b and 8a had improved chemical properties while still maintaining inhibitory activity against mTORC1. The results suggest a new strategy for the discovery of novel drug candidates and the treatment of diverse mTORC1-related diseases.

Keywords: Leucyl-tRNA synthetase (LRS); Protein-protein interaction; Pyrazolone; RagD; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Leucine-tRNA Ligase / antagonists & inhibitors*
  • Leucine-tRNA Ligase / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors*
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Molecular Structure
  • Monomeric GTP-Binding Proteins / antagonists & inhibitors*
  • Monomeric GTP-Binding Proteins / metabolism
  • Pyrazolones / chemical synthesis
  • Pyrazolones / chemistry
  • Pyrazolones / pharmacology*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Pyrazolones
  • RRAGD protein, human
  • pyrazolone
  • Mechanistic Target of Rapamycin Complex 1
  • Monomeric GTP-Binding Proteins
  • Leucine-tRNA Ligase