Structure and Property Guided Design in the Identification of PRMT5 Tool Compound EPZ015666

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• 作者：Kenneth W. Duncan ; Nathalie Rioux ; P. Ann Boriack-Sjodin ; Michael J. Munchhof ; Lawrence A. Reiter ; Christina R. Majer ; Lei Jin ; L. Danielle Johnston ; Elayne Chan-Penebre ; Kristy G. Kuplast ; Margaret Porter Scott ; Roy M. Pollock ; Nigel J. Waters ; Jesse J. Smith ; Mikel P. Moyer ; Robert A. Copeland ; Richard Chesworth
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：February 11, 2016
• 年：2016
• 卷：7
• 期：2
• 页码：162-166
• 全文大小：407K
• ISSN：1948-5875

文摘

The recent publication of a potent and selective inhibitor of protein methyltransferase 5 (PRMT5) provides the scientific community with in vivo-active tool compound EPZ015666 (GSK3235025) to probe the underlying pharmacology of this key enzyme. Herein, we report the design and optimization strategies employed on an initial hit compound with poor in vitro clearance to yield in vivo tool compound EPZ015666 and an additional potent in vitro tool molecule EPZ015866 (GSK3203591).