Discovery of a chemical probe for PRDM9

Nat Commun. 2019 Dec 17;10(1):5759. doi: 10.1038/s41467-019-13652-x.


PRDM9 is a PR domain containing protein which trimethylates histone 3 on lysine 4 and 36. Its normal expression is restricted to germ cells and attenuation of its activity results in altered meiotic gene transcription, impairment of double-stranded breaks and pairing between homologous chromosomes. There is growing evidence for a role of aberrant expression of PRDM9 in oncogenesis and genome instability. Here we report the discovery of MRK-740, a potent (IC50: 80 ± 16 nM), selective and cell-active PRDM9 inhibitor (Chemical Probe). MRK-740 binds in the substrate-binding pocket, with unusually extensive interactions with the cofactor S-adenosylmethionine (SAM), conferring SAM-dependent substrate-competitive inhibition. In cells, MRK-740 specifically and directly inhibits H3K4 methylation at endogenous PRDM9 target loci, whereas the closely related inactive control compound, MRK-740-NC, does not. The discovery of MRK-740 as a chemical probe for the PRDM subfamily of methyltransferases highlights the potential for exploiting SAM in targeting SAM-dependent methyltransferases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Crystallography, X-Ray
  • DNA Methylation / drug effects
  • Drug Discovery / methods*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • HEK293 Cells
  • Histone-Lysine N-Methyltransferase / antagonists & inhibitors*
  • Histone-Lysine N-Methyltransferase / metabolism
  • Histone-Lysine N-Methyltransferase / ultrastructure
  • Histones / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Molecular Dynamics Simulation
  • Molecular Probes / chemistry
  • Molecular Probes / pharmacology*
  • Protein Domains
  • S-Adenosylmethionine / metabolism


  • Enzyme Inhibitors
  • Histones
  • Molecular Probes
  • histone H3 trimethyl Lys4
  • S-Adenosylmethionine
  • Histone-Lysine N-Methyltransferase
  • PRDM9 protein, human