Covalent inhibitors of EZH2: Design, synthesis and evaluation - 13/02/22
, Luoting Yu a, ⁎ Bienvenido a EM-consulte, la referencia de los profesionales de la salud.
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Abstract |
The histone lysine methyltransferase EZH2 has been implicated as a key component in cancer development. Up to date, there are only a few EZH2 covalent inhibitors. In this study, a new series of 3-acrylamido-2-methyl-N-((2-oxo-1,2-dihydropyridin-3-yl) methyl) benzamide derivatives were designed, synthesized, and demonstrated to act as EZH2 covalent inhibitors, among which SKLB-03176 was the most potent compound. SAM competition experiments, mass spectrometry, and washing-out assays proved that SKLB-03176 could covalently bind to the SAM pocket of EZH2. Remarkably, SKLB-03176 exhibited weak activity against other targets, such as 5 histone methyltransferases and more than 30 kinases. Besides, it could inhibit the activity of a variety of EZH2 mutants and significantly inhibit the expression of H3K27Me3 in cells. Furthermore, SKLB-03176 showed no cytotoxicity to normal cells. Our data suggested that SKLB-03176 could be used as a promising lead compound for the development of new EZH2 covalent inhibitors and a valuable chemical tool to study the biological functions of EZH2 or PRC2.
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Highlights |
• | A series of novel EZH2 covalent inhibitors have been designed and synthesized. |
• | SKLB-03176 exhibited weak activity against other HMTs and more than 30 kinases. |
• | SKLB-03176 showed no cytotoxicity to normal cells. |
• | SKLB-03176 could be used as a valuable chemical tool. |
Keywords : EZH2, Histone methylation, Covalent inhibitor, Anti-cancer agents
Esquema
Vol 147
Artículo 112617- mars 2022 Regresar al número
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Bienvenido a EM-consulte, la referencia de los profesionales de la salud.
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