Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein.
Corentin BonYang SiMelanie PernakMagdalena BarbachowskaEva Levi-AcobasVeronique Cadet DanielCorinne JalletDusan RuzicNemanja DjokovicTeodora Djikic-StojsicKatarina NikolicLudovic HalbyPaola Barbara ArimondoPublished in: Molecules (Basel, Switzerland) (2021)
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.
Keyphrases
- induced apoptosis
- small molecule
- cell cycle arrest
- dna methylation
- clinical trial
- acute myeloid leukemia
- signaling pathway
- endoplasmic reticulum stress
- protein protein
- gene expression
- genome wide
- cystic fibrosis
- cell death
- energy transfer
- staphylococcus aureus
- nitric oxide
- escherichia coli
- pseudomonas aeruginosa
- drug delivery
- cancer therapy
- drug induced
- combination therapy