Identification and characterization of second-generation EZH2 inhibitors with extended residence times and improved biological activity.

ABSTRACT: The histone methyltransferase EZH2 has been the target of numerous small-molecule inhibitor discovery efforts over the last 10+ years. Emerging clinical data have provided early evidence for single agent activity with acceptable safety profiles for first-generation inhibitors. We have developed kinetic methodologies for studying EZH2-inhibitor-binding kinetics that have allowed us to identify a unique structural modification that results in significant increases in the drug-target residence times of all EZH2 inhibitor scaffolds we have studied. The unexpected residence time enhancement bestowed by this modification has enabled us to create a series of second-generation EZH2 inhibitors with sub-pM binding affinities. We provide both biophysical evidence validating this sub-pM potency and bi

SUBMITTER: Stuckey JI 

PROVIDER: S-EPMC7949150 | biostudies-literature | 2021 Jan-Jun

REPOSITORIES: biostudies-literature