TY  - JOUR
AU  - Bon, Corentin
AU  - Si, Yang
AU  - Pernak, Melanie
AU  - Barbachowska, Magdalena
AU  - Levi-Acobas, Eva
AU  - Cadet Daniel, Veronique
AU  - Jallet, Corinne
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Đikić, Teodora
AU  - Nikolić, Katarina
AU  - Halby, Ludovic
AU  - Arimondo, Paola B.
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3954
AB  - 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.
PB  - MDPI
T2  - Molecules
T1  - Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein
VL  - 26
IS  - 17
DO  - 10.3390/molecules26175300
ER  - 

@article{
author = "Bon, Corentin and Si, Yang and Pernak, Melanie and Barbachowska, Magdalena and Levi-Acobas, Eva and Cadet Daniel, Veronique and Jallet, Corinne and Ružić, Dušan and Đoković, Nemanja and Đikić, Teodora and Nikolić, Katarina and Halby, Ludovic and Arimondo, Paola B.",
year = "2021",
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.",
publisher = "MDPI",
journal = "Molecules",
title = "Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein",
volume = "26",
number = "17",
doi = "10.3390/molecules26175300"
}

Bon, C., Si, Y., Pernak, M., Barbachowska, M., Levi-Acobas, E., Cadet Daniel, V., Jallet, C., Ružić, D., Đoković, N., Đikić, T., Nikolić, K., Halby, L.,& Arimondo, P. B.. (2021). Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein. in Molecules
MDPI., 26(17).
https://doi.org/10.3390/molecules26175300

Bon C, Si Y, Pernak M, Barbachowska M, Levi-Acobas E, Cadet Daniel V, Jallet C, Ružić D, Đoković N, Đikić T, Nikolić K, Halby L, Arimondo PB. Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein. in Molecules. 2021;26(17).
doi:10.3390/molecules26175300 .

Bon, Corentin, Si, Yang, Pernak, Melanie, Barbachowska, Magdalena, Levi-Acobas, Eva, Cadet Daniel, Veronique, Jallet, Corinne, Ružić, Dušan, Đoković, Nemanja, Đikić, Teodora, Nikolić, Katarina, Halby, Ludovic, Arimondo, Paola B., "Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein" in Molecules, 26, no. 17 (2021),
https://doi.org/10.3390/molecules26175300 . .