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© Research
Publication : Molecules

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

Scientific Fields
Diseases
Organisms
Applications
Technique

Published in Molecules - 31 Aug 2021

Corentin BON, Yang SI, Melanie PERNAK, Magdalena Barbachowska, Eva Levi-Acobas, Veronique Cadet Daniel, Corinne Jallet, Dusan Ruzic, Nemanja Djokovic,Teodora Djikić, Katarina Nikolic, Ludovic Halby, , Paola B Arimondo

Link to DOI – 10.3390/molecules26175300

Bon, C.et al. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein. Molecules 2021, 26 (17), 5300. https://doi.org/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 methyl-ation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.

https://www.researchgate.net/publication/354248306_Synthesis_and_Biological_Activity_of_a_Cytostatic_Inhibitor_of_MLLr_Leukemia_Targeting_the_DOT1L_Protein