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

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.
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Submitted on : Tuesday, November 2, 2021 - 3:56:07 PM
Last modification on : Thursday, April 7, 2022 - 1:58:35 PM
Long-term archiving on: : Thursday, February 3, 2022 - 7:27:48 PM


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Corentin Bon, Yang Si, Melanie Pernak, Magdalena Barbachowska, Eva Levi-Acobas, et al.. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein. Molecules, MDPI, 2021, Special Issue The Chemical Biology Research in France, 26 (17), pp.5300. ⟨10.3390/molecules26175300⟩. ⟨pasteur-03411876⟩



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