Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2

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• 作者：Erik Eggert ; Roman C. Hillig ; Silke Koehr ; Detlef Stöckigt ; Jörg Weiske ; Naomi Barak ; Jeffrey Mowat ; Thomas Brumby ; Clara D. Christ ; Antonius ter Laak ; Tina Lang ; Amaury E. Fernandez-Montalvan ; Volker Badock ; Hilmar Weinmann ; Ingo V. Hartung ; Dalia Barsyte-Lovejoy ; Magdalena Szewczyk ; Steven Kennedy ; Fengling Li ; Masoud Vedadi ; Peter J. Brown ; Vijayaratnam Santhakumar ; Cheryl H. Arrowsmith ; Timo Stellfeld ; Carlo Stresemann
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：May 26, 2016
• 年：2016
• 卷：59
• 期：10
• 页码：4578-4600
• 全文大小：1283K
• 年卷期：0
• ISSN：1520-4804

文摘

Protein lysine methyltransferases have recently emerged as a new target class for the development of inhibitors that modulate gene transcription or signaling pathways. SET and MYND domain containing protein 2 (SMYD2) is a catalytic SET domain containing methyltransferase reported to monomethylate lysine residues on histone and nonhistone proteins. Although several studies have uncovered an important role of SMYD2 in promoting cancer by protein methylation, the biology of SMYD2 is far from being fully understood. Utilization of highly potent and selective chemical probes for target validation has emerged as a concept which circumvents possible limitations of knockdown experiments and, in particular, could result in an improved exploration of drug targets with a complex underlying biology. Here, we report the development of a potent, selective, and cell-active, substrate-competitive inhibitor of SMYD2, which is the first reported inhibitor suitable for in vivo target validation studies in rodents.