2. Academic Validation
  3. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein

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

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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