Open AccessDesign, Synthesis, and Pharmacological Evaluation of Second Generation EZH2 Inhibitors with Long Residence Time
Author(s) -
Avinash Khanna,
Alexandre Côté,
Shilpi Arora,
Ludivine Moine,
Victor S. Gehling,
Jehrod B. Brenneman,
Nico Cantone,
Jacob I. Stuckey,
Shruti Apte,
Ashwin Ramakrishnan,
Kamil Bruderek,
William D. Bradley,
James E. Audia,
Richard Cummings,
Robert J. Sims,
Patrick Trojer,
Julian Levell
Publication year - 2020
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.0c00045
Subject(s) - ezh2 , prc2 , histone methyltransferase , histone , histone h3 , methylation , methyltransferase , protein subunit , chemistry , cancer research , histone methylation , medicine , biochemistry , dna methylation , gene expression , gene
Histone methyltransferase EZH2, which is the catalytic subunit of the PRC2 complex, catalyzes the methylation of histone H3K27-a transcriptionally repressive post-translational modification (PTM). EZH2 is commonly mutated in hematologic malignancies and frequently overexpressed in solid tumors, where its expression level often correlates with poor prognosis. First generation EZH2 inhibitors are beginning to show clinical benefit, and we believe that a second generation EZH2 inhibitor could further build upon this foundation to fully realize the therapeutic potential of EZH2 inhibition. During our medicinal chemistry campaign, we identified 4-thiomethyl pyridone as a key modification that led to significantly increased potency and prolonged residence time. Leveraging this finding, we optimized a series of EZH2 inhibitors, with enhanced antitumor activity and improved physiochemical properties, which have the potential to expand the clinical use of EZH2 inhibition.