Diverse Chemical Scaffolds Enhance Oligodendrocyte Formation by Inhibiting CYP51, TM7SF2, or EBP

Cell Chem Biol. 2019 Apr 18;26(4):593-599.e4. doi: 10.1016/j.chembiol.2019.01.004. Epub 2019 Feb 14.

Abstract

Small molecules that promote oligodendrocyte formation have been identified in "drug repurposing" screens to nominate candidate therapeutics for diseases in which myelin is lost, including multiple sclerosis. We recently reported that many such molecules enhance oligodendrocyte formation not by their canonical targets but by inhibiting a narrow range of enzymes in cholesterol biosynthesis. Here we identify enhancers of oligodendrocyte formation obtained by screening a structurally diverse library of 10,000 small molecules. Identification of the cellular targets of these validated hits revealed a majority inhibited the cholesterol biosynthesis enzymes CYP51, TM7SF2, or EBP. In addition, evaluation of analogs led to identification of CW3388, a potent EBP-inhibiting enhancer of oligodendrocyte formation poised for further optimization.

Keywords: cholesterol; glial biology; high-content imaging; multiple sclerosis; oligodendrocyte; phenotypic screening; remyelination; sterol signaling; target identification.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-alpha Demethylase Inhibitors / chemistry
  • 14-alpha Demethylase Inhibitors / pharmacology*
  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Mice
  • Oligodendroglia / cytology
  • Oligodendroglia / drug effects*
  • Oligodendroglia / metabolism
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Steroid Isomerases / antagonists & inhibitors*
  • Steroid Isomerases / metabolism

Substances

  • 14-alpha Demethylase Inhibitors
  • Small Molecule Libraries
  • Oxidoreductases
  • delta(14)-sterol reductase
  • Ebp protein, mouse
  • Steroid Isomerases