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Article

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

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
*
Author to whom correspondence should be addressed.
Academic Editor: Katherine Seley-Radtke
Molecules 2021, 26(17), 5300; https://doi.org/10.3390/molecules26175300
Received: 15 July 2021 / Revised: 5 August 2021 / Accepted: 25 August 2021 / Published: 31 August 2021
(This article belongs to the Special Issue The Chemical Biology Research in France)
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. View Full-Text
Keywords: MLL rearranged leukemia; DOT1L; histone methylation; rational drug design; HMT inhibitors; bisubstrates MLL rearranged leukemia; DOT1L; histone methylation; rational drug design; HMT inhibitors; bisubstrates
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MDPI and ACS Style

Bon, C.; Si, Y.; Pernak, M.; Barbachowska, M.; Levi-Acobas, E.; Cadet Daniel, V.; Jallet, C.; Ruzic, D.; Djokovic, N.; Djikić, T.; Nikolic, K.; Halby, L.; Arimondo, P.B. Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein. Molecules 2021, 26, 5300. https://doi.org/10.3390/molecules26175300

AMA Style

Bon C, Si Y, Pernak M, Barbachowska M, Levi-Acobas E, Cadet Daniel V, Jallet C, Ruzic D, Djokovic N, Djikić T, Nikolic K, Halby L, Arimondo PB. 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

Chicago/Turabian Style

Bon, Corentin, Yang Si, Melanie Pernak, Magdalena Barbachowska, Eva Levi-Acobas, Veronique Cadet Daniel, Corinne Jallet, Dusan Ruzic, Nemanja Djokovic, Teodora Djikić, Katarina Nikolic, Ludovic Halby, and Paola B. Arimondo 2021. "Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein" Molecules 26, no. 17: 5300. https://doi.org/10.3390/molecules26175300

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