| Literature DB >> 26769278 |
Kevin W Kuntz1, John E Campbell1, Heike Keilhack1, Roy M Pollock1, Sarah K Knutson1, Margaret Porter-Scott1, Victoria M Richon1, Chris J Sneeringer1, Tim J Wigle1, Christina J Allain1, Christina R Majer1, Mikel P Moyer1, Robert A Copeland1, Richard Chesworth1.
Abstract
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.Entities:
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Year: 2016 PMID： 26769278 DOI： 10.1021/acs.jmedchem.5b01501
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446