Publication details

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

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KHIRSARIYA PrashantKumar POSPÍŠIL Patrik MAIER Lukáš BOUDNÝ Miroslav BABÁŠ Martin KROUTIL Ondřej MRÁZ Marek VÁCHA Robert PARUCH Kamil

Year of publication 2022
Type Article in Periodical
Magazine / Source Journal of Medicinal Chemistry
MU Faculty or unit

Faculty of Science

Keywords Molecular structure; Genetics; Ethanol; Inhibitors; Assays; leukemia; DOT1L
Description 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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