New small molecule inhibitors of histone methyl transferase DOT1L with a nitrile as a non-traditional replacement for heavy halogen atoms

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• 作者：Sophie S. Spurr^a ; Elliott D. Bayle^a ; Wenyu Yu^b ; Fengling Li^b ; Wolfram Tempel^b ; Masoud Vedadi^b ; ^c ; Matthieu Schapira^b ; ^c ; Paul V. Fish^a ; ^{p.fish@ucl.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Protein methyltransferase ; DOT1L inhibitors ; Toyocamycin ; Bioisostere ; Cyano-deaza-SAH
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：15 September 2016
• 年：2016
• 卷：26
• 期：18
• 页码：4518-4522
• 全文大小：697 K

文摘

A number of new nucleoside derivatives are disclosed as inhibitors of DOT1L activity. SARs established that DOT1L inhibition could be achieved through incorporation of polar groups and small heterocycles at the 5-position (5, 6, 12) or by the application of alternative nitrogenous bases (18). Based on these results, CN-SAH (19) was identified as a potent and selective inhibitor of DOT1L activity where the polar 5-nitrile group was shown by crystallography to bind in the hydrophobic pocket of DOT1L. In addition, we show that a polar nitrile group can be used as a non-traditional replacement for heavy halogen atoms.