| KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA and Kamil PARUCH. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. Journal of Medicinal Chemistry. Washington: American Chemical Society, 2022, vol. 65, No 7, p. 5701-5723. ISSN 0022-2623. Available from: https://dx.doi.org/10.1021/acs.jmedchem.1c02228. |
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@article{1854512,
author = {Khirsariya, PrashantKumar and Pospíšil, Patrik and Maier, Lukáš and Boudný, Miroslav and Babáš, Martin and Kroutil, Ondřej and Mráz, Marek and Vácha, Robert and Paruch, Kamil},
article_location = {Washington},
article_number = {7},
doi = {http://dx.doi.org/10.1021/acs.jmedchem.1c02228},
keywords = {Molecular structure; Genetics; Ethanol; Inhibitors; Assays; leukemia; DOT1L},
language = {eng},
issn = {0022-2623},
journal = {Journal of Medicinal Chemistry},
title = {Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides},
url = {https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c02228},
volume = {65},
year = {2022}
}
TY - JOUR
ID - 1854512
AU - Khirsariya, PrashantKumar - Pospíšil, Patrik - Maier, Lukáš - Boudný, Miroslav - Babáš, Martin - Kroutil, Ondřej - Mráz, Marek - Vácha, Robert - Paruch, Kamil
PY - 2022
TI - Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides
JF - Journal of Medicinal Chemistry
VL - 65
IS - 7
SP - 5701-5723
EP - 5701-5723
PB - American Chemical Society
SN - 00222623
KW - Molecular structure
KW - Genetics
KW - Ethanol
KW - Inhibitors
KW - Assays
KW - leukemia
KW - DOT1L
UR - https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c02228
N2 - Histone methyltransferase DOT1L is an attractive therapeutic target for the treatment of hematological malignancies. Here, we report the design, synthesis, and profiling of new DOT1L inhibitors based on nonroutine carbocyclic C-nucleoside scaffolds. The experimentally observed SAR was found to be nontrivial as seemingly minor changes of individual substituents resulted in significant changes in the affinity to DOT1L. Molecular modeling suggested that these trends could be related to significant conformational changes of the protein upon interaction with the inhibitors. The compounds 22 and (−)-53 (MU1656), carbocyclic C-nucleoside analogues of the natural nucleoside derivative EPZ004777, and the clinical candidate EPZ5676 (pinometostat) potently and selectively inhibit DOT1L in vitro as well as in the cell. The most potent compound MU1656 was found to be more metabolically stable and significantly less toxic in vivo than pinometostat itself.
ER -
KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA and Kamil PARUCH. Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides. \textit{Journal of Medicinal Chemistry}. Washington: American Chemical Society, 2022, vol.~65, No~7, p.~5701-5723. ISSN~0022-2623. Available from: https://dx.doi.org/10.1021/acs.jmedchem.1c02228.
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