Synthesis and Profiling of Highly Selective Inhibitors of Methyltransferase DOT1L Based on Carbocyclic C-Nucleosides

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Publikace nespadá pod Ekonomicko-správní fakultu, ale pod Přírodovědeckou fakultu. Oficiální stránka publikace je na webu muni.cz.
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KHIRSARIYA PrashantKumar POSPÍŠIL Patrik MAIER Lukáš BOUDNÝ Miroslav BABÁŠ Martin KROUTIL Ondřej MRÁZ Marek VÁCHA Robert PARUCH Kamil

Rok publikování 2022
Druh Článek v odborném periodiku
Časopis / Zdroj Journal of Medicinal Chemistry
Fakulta / Pracoviště MU

Přírodovědecká fakulta

Citace
www https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.1c02228
Doi http://dx.doi.org/10.1021/acs.jmedchem.1c02228
Klíčová slova Molecular structure; Genetics; Ethanol; Inhibitors; Assays; leukemia; DOT1L
Popis 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.
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