TY  - JOUR
AU  - Bon, Corentin
AU  - Barbachowska, Magdalena
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Si, Yang
AU  - Soresinetti, Laura
AU  - Jallet, Corinne
AU  - Tafit, Ambre
AU  - Halby, Ludovic
AU  - Nikolić, Katarina
AU  - Arimondo, Paola B
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4908
AB  - Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.
PB  - Newlands Press
T2  - Future Medicinal Chemistry
T1  - Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies
VL  - 14
VL  - 557
VL  - 570
IS  - 8
DO  - 10.4155/fmc-2021-0251
ER  - 

@article{
author = "Bon, Corentin and Barbachowska, Magdalena and Đoković, Nemanja and Ružić, Dušan and Si, Yang and Soresinetti, Laura and Jallet, Corinne and Tafit, Ambre and Halby, Ludovic and Nikolić, Katarina and Arimondo, Paola B",
year = "2022",
abstract = "Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.",
publisher = "Newlands Press",
journal = "Future Medicinal Chemistry",
title = "Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies",
volume = "14, 557, 570",
number = "8",
doi = "10.4155/fmc-2021-0251"
}

Bon, C., Barbachowska, M., Đoković, N., Ružić, D., Si, Y., Soresinetti, L., Jallet, C., Tafit, A., Halby, L., Nikolić, K.,& Arimondo, P. B.. (2022). Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies. in Future Medicinal Chemistry
Newlands Press., 14(8).
https://doi.org/10.4155/fmc-2021-0251

Bon C, Barbachowska M, Đoković N, Ružić D, Si Y, Soresinetti L, Jallet C, Tafit A, Halby L, Nikolić K, Arimondo PB. Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies. in Future Medicinal Chemistry. 2022;14(8).
doi:10.4155/fmc-2021-0251 .

Bon, Corentin, Barbachowska, Magdalena, Đoković, Nemanja, Ružić, Dušan, Si, Yang, Soresinetti, Laura, Jallet, Corinne, Tafit, Ambre, Halby, Ludovic, Nikolić, Katarina, Arimondo, Paola B, "Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies" in Future Medicinal Chemistry, 14, no. 8 (2022),
https://doi.org/10.4155/fmc-2021-0251 . .

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 . .