Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein

Molecules. 2021 Aug 31;26(17):5300. doi: 10.3390/molecules26175300.


Histone methyltransferase DOT1L catalyzes mono-, di- and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.

Keywords: DOT1L; HMT inhibitors; MLL rearranged leukemia; bisubstrates; histone methylation; rational drug design.

MeSH terms

  • Cytostatic Agents / therapeutic use*
  • Histone-Lysine N-Methyltransferase / metabolism*
  • Histones / metabolism*
  • Humans
  • Leukemia / drug therapy
  • Leukemia / metabolism
  • Methylation / drug effects
  • Molecular Structure


  • Cytostatic Agents
  • Histones
  • DOT1L protein, human
  • Histone-Lysine N-Methyltransferase