Aberrant
gene-silencing through dysregulation of polycomb protein
activity has emerged as an important oncogenic mechanism in cancer,
implicating polycomb proteins as important therapeutic targets. Recently,
an inhibitor targeting EZH2, the methyltransferase component of PRC2,
received U.S. Food and Drug Administration approval following promising
clinical responses in cancer patients. However, the current array
of EZH2 inhibitors have poor brain penetrance, limiting their use
in patients with central nervous system malignancies, a number of
which have been shown to be sensitive to EZH2 inhibition. To address
this need, we have identified a chemical strategy, based on computational
modeling of pyridone-containing EZH2 inhibitor scaffolds, to minimize
P-glycoprotein activity, and here we report the first brain-penetrant
EZH2 inhibitor, TDI-6118 (compound 5). Additionally,
in the course of our attempts to optimize this compound, we discovered
TDI-11904 (compound 21), a novel, highly potent, and
peripherally active EZH2 inhibitor based on a 7 member ring structure.