The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat

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.