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

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

  • J Biol Chem. 2021 Jan-Jun;296:100349. doi: 10.1016/j.jbc.2021.100349.
Jacob I Stuckey 1,  Nico R Cantone 1,  Alexandre Côté 1,  Shilpi Arora 1,  Valerie Vivat 1,  Ashwin Ramakrishnan 1,  Jennifer A Mertz 1,  Avinash Khanna 1,  Jehrod Brenneman 1,  Victor S Gehling 1,  Ludivine Moine 1,  Robert J Sims 3rd 1,  James E Audia 1,  Patrick Trojer 1,  Julian R Levell 1,  Richard T Cummings 2
Affiliations

Affiliations

  • 1 Constellation Pharmaceuticals, Cambridge, Massachusetts, USA.
  • 2 Constellation Pharmaceuticals, Cambridge, Massachusetts, USA. Electronic address: richard.cummings@constellationpharma.com.
PMID: 33524394 DOI: 10.1016/j.jbc.2021.100349
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.

Keywords

EZH2; TR-FRET-binding kinetics; femtomolar; residence time; small-molecule kinetics.

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