Synthesis and structure-activity relationship investigation of adenosine-containing inhibitors of histone methyltransferase DOT1L

J Med Chem. 2012 Sep 27;55(18):8066-74. doi: 10.1021/jm300917h. Epub 2012 Sep 6.


Histone3-lysine79 (H3K79) methyltransferase DOT1L has been found to be a drug target for acute leukemia with MLL (mixed lineage leukemia) gene translocations. A total of 55 adenosine-containing compounds were designed and synthesized, among which several potent DOT1L inhibitors were identified with K(i) values as low as 0.5 nM. These compounds also show high selectivity (>4500-fold) over three other histone methyltransferases. Structure-activity relationships (SAR) of these compounds for their inhibitory activities against DOT1L are discussed. Potent DOT1L inhibitors exhibit selective activity against the proliferation of MLL-translocated leukemia cell lines MV4;11 and THP1 with EC(50) values of 4-11 μM. Isothermal titration calorimetry studies showed that two representative inhibitors bind with a high affinity to the DOT1L:nucleosome complex and only compete with the enzyme cofactor SAM (S-adenosyl-L-methionine) but not the substrate nucleosome.

Publication types

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

MeSH terms

  • Adenosine / chemical synthesis*
  • Adenosine / chemistry
  • Adenosine / metabolism
  • Adenosine / pharmacology*
  • Chemistry Techniques, Synthetic
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Methyltransferases / antagonists & inhibitors*
  • Methyltransferases / chemistry
  • Methyltransferases / metabolism
  • Molecular Docking Simulation
  • Protein Conformation
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Adenosine