KHIRSARIYA, PrashantKumar, Patrik POSPÍŠIL, Lukáš MAIER, Miroslav BOUDNÝ, Martin BABÁŠ, Ondřej KROUTIL, Marek MRÁZ, Robert VÁCHA a 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, roč. 65, č. 7, s. 5701-5723. ISSN 0022-2623. Dostupné z: 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 a 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, roč.~65, č.~7, s.~5701-5723. ISSN~0022-2623. Dostupné z: https://dx.doi.org/10.1021/acs.jmedchem.1c02228.
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