1. Identification and characterization of second-generation EZH2 inhibitors with extended residence times and improved biological activity.
- Author
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Stuckey JI, Cantone NR, Côté A, Arora S, Vivat V, Ramakrishnan A, Mertz JA, Khanna A, Brenneman J, Gehling VS, Moine L, Sims RJ 3rd, Audia JE, Trojer P, Levell JR, and Cummings RT
- Subjects
- Allosteric Regulation drug effects, Animals, Drug Discovery, Enhancer of Zeste Homolog 2 Protein metabolism, Female, HeLa Cells, Humans, Mice, SCID, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Mice, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Enzyme Inhibitors chemistry, Enzyme Inhibitors pharmacology
- 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 biological evidence demonstrating the utility and relevance of such high-affinity interactions with EZH2., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2021
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