Discovery of the First-in-Class G9a/GLP PROTAC Degrader

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2024 Apr 11

PMID 38602846

Authors

Julia Velez

Yulin Han

Hyerin Yim

Peiyi Yang

Zhijie Deng

Kwang-Su Park

Md Kabir

H Umit Kaniskan

Yan Xiong

Jian Jin

Affiliations

Soon will be listed here.

Abstract

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and dimethylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and noncatalytic oncogenic functions of G9a/GLP. As such, G9a/GLP catalytic inhibitors have displayed limited anticancer activity. Here, we report the discovery of the first-in-class G9a/GLP proteolysis targeting chimera (PROTAC) degrader (MS8709), as a potential anticancer therapeutic. induces G9a/GLP degradation in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Futhermore, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, displays superior cell growth inhibition to the parent G9a/GLP inhibitor UNC0642 in prostate, leukemia, and lung cancer cells and has suitable mouse pharmacokinetic properties for in vivo efficacy studies. Overall, is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers.

Citing Articles

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