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

Corentin Bon (1) , Yang Si (1) , Melanie Pernak (1) , Magdalena Barbachowska (1) , Eva Levi-Acobas (1) , Veronique Cadet Daniel (1) , Corinne Jallet (1) , Dusan Ruzic (2) , Nemanja Djokovic (2) , Teodora Djikić (2) , Katarina Nikolic (2) , Ludovic Halby (1) , Paola B Arimondo (1)

1 EpiCBio - Chimie biologique épigénétique - Epigenetic Chemical Biology
2 University of Belgrade [Belgrade]

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.

Mots clés: DOT1L; HMT inhibitors; MLL rearranged leukemia; bisubstrates; histone methylation; rational drug design

Domaines: Sciences du Vivant [q-bio]

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, 2021, Special Issue The Chemical Biology Research in France, 26 (17), pp.5300. ⟨10.3390/molecules26175300⟩. ⟨pasteur-03411876⟩