Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein
Authors
Bon, CorentinSi, 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.
Article (Published version)
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Show full item recordAbstract
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.
Keywords:
Bisubstrates / DOT1L / Histone methylation / HMT inhibitors / MLL rearranged leukemia / Rational drug designSource:
Molecules, 2021, 26, 17Publisher:
- MDPI
Funding / projects:
- Le Comitéde Paris de la Ligue contre la Cancer (project Epi-Med 2020-2021) to PBA.
- Hubert Curien Partnership Project for collaboration France-Serbia 2020- 2022 (Program Pavle Savic 2020) to PBA and KN
- EU COST CM1406 Epigenetic Chemical Biology program.
DOI: 10.3390/molecules26175300
ISSN: 1420-3049
WoS: 000694318800001
Scopus: 2-s2.0-85114232085
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Institution/Community
PharmacyTY - 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 . .