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.
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 . .
