Development of 5-hydroxypyrazole derivatives as reversible inhibitors of lysine specific demethylase 1

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3190-3195. doi: 10.1016/j.bmcl.2017.05.018. Epub 2017 May 8.

Abstract

A series of reversible inhibitors of lysine specific demethylase 1 (LSD1) with a 5-hydroxypyrazole scaffold have been developed from compound 7, which was identified from the patent literature. Surface plasmon resonance (SPR) and biochemical analysis showed it to be a reversible LSD1 inhibitor with an IC50 value of 0.23µM. Optimisation of this compound by rational design afforded compounds with Kd values of <10nM. In human THP-1 cells, these compounds were found to upregulate the expression of the surrogate cellular biomarker CD86. Compound 11p was found to have moderate oral bioavailability in mice suggesting its potential for use as an in vivo tool compound.

Keywords: Acute myeloid leukaemia; Cancer therapy; Epigenetic therapy; Epigenetics; KDM1A; LSD1; Reversible inhibitor; Stem cell differentiation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-2 Antigen / metabolism
  • Binding Sites
  • Catalytic Domain
  • Cell Differentiation / drug effects
  • Cell Line
  • Half-Life
  • Histone Demethylases / antagonists & inhibitors*
  • Histone Demethylases / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Mice
  • Molecular Docking Simulation
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / pharmacology
  • Structure-Activity Relationship
  • Surface Plasmon Resonance

Substances

  • B7-2 Antigen
  • Pyrazoles
  • Histone Demethylases
  • KDM1A protein, human