Synthesis and Biological Activity of a Cytostatic Inhibitor of MLLr Leukemia Targeting the DOT1L Protein.
DOT1L
HMT inhibitors
MLL rearranged leukemia
bisubstrates
histone methylation
rational drug design
Journal
Molecules (Basel, Switzerland)
ISSN: 1420-3049
Titre abrégé: Molecules
Pays: Switzerland
ID NLM: 100964009
Informations de publication
Date de publication:
31 Aug 2021
31 Aug 2021
Historique:
received:
15
07
2021
revised:
05
08
2021
accepted:
25
08
2021
entrez:
10
9
2021
pubmed:
11
9
2021
medline:
15
12
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34500733
pii: molecules26175300
doi: 10.3390/molecules26175300
pmc: PMC8434109
pii:
doi:
Substances chimiques
Cytostatic Agents
0
Histones
0
DOT1L protein, human
EC 2.1.1.-
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Région Ile de France
ID : ARDoC
Organisme : DIM OneHealth Investissement
ID : EpiK
Organisme : Comité de Paris de la Ligue contre la Cancer
ID : Epi-Med 2020-2021
Organisme : Program Pavle Savic 2020
ID : Hubert Curien Partnership Project
Organisme : European Cooperation in Science and Technology
ID : CM1406 Epigenetic Chemical Biology
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