Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein |
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| Authors: | Corentin Bon Yang Si Melanie Pernak Magdalena Barbachowska Eva Levi-Acobas Veronique Cadet Daniel Corinne Jallet Dusan Ruzic Nemanja Djokovic Teodora Djiki&#x; Katarina Nikolic Ludovic Halby Paola B Arimondo |
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| Institution: | 1.Epigenetic Chemical Biology, Department of Structural Biology and Chemistry, Institut Pasteur, UMR3523 CNRS, 75015 Paris, France; (C.B.); (Y.S.); (M.P.); (M.B.); (E.L.-A.); (V.C.D.); (C.J.); (L.H.);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; (D.R.); (N.D.); (T.D.); (K.N.) |
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| 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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| Keywords: | MLL rearranged leukemia DOT1L histone methylation rational drug design HMT inhibitors bisubstrates |
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