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.
Corentin Bon  1  2 ,  Yang Si  1 ,  Melanie Pernak  1 ,  Magdalena Barbachowska  1  2 ,  Eva Levi-Acobas  1 ,  Veronique Cadet Daniel  1 ,  Corinne Jallet  1 ,  Dusan Ruzic  3 ,  Nemanja Djokovic  3 ,  Teodora Djikić  3 ,  Katarina Nikolic  3 ,  Ludovic Halby  1 ,  Paola B Arimondo  1
Affiliations
  • 1. Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS, 75015 Paris, France.
  • 2. Ecole Doctorale MTCI, Université de Paris, Sorbonne Paris Cité, 75006 Paris, France.
  • 3. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia.
PMID: 34500733 DOI: 10.3390/molecules26175300
Abstract

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.
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