The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat
详细信息 查看全文
- 作者：Kevin W. Kuntz ; John E. Campbell ; Heike Keilhack ; Roy M. Pollock ; Sarah K. Knutson ; Margaret Porter-Scott ; Victoria M. Richon ; Chris J. Sneeringer ; Tim J. Wigle ; Christina J. Allain ; Christina R. Majer ; Mikel P. Moyer ; Robert A. Copeland ; Richard Chesworth
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：February 25, 2016
- 年：2016
- 卷：59
- 期：4
- 页码：1556-1564
- 全文大小：397K
- ISSN：1520-4804
文摘
Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure–activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.