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

• Main Authors: 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
• Format: Article
• Language: English
• Published: MDPI AG 2021-08-01
• Series: Molecules
• Subjects: MLL rearranged leukemia; DOT1L; histone methylation; rational drug design; HMT inhibitors; bisubstrates
• Online Access: https://www.mdpi.com/1420-3049/26/17/5300

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.