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bioRxiv · 10.1101/2024.02.26.582210

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

Velez, J.·Han, Y.·Yim, H.·Yang, P.·Deng, Z.·Park, K.·Kabir, M.·Kaniskan, H.·Xiong, Y.·Jin, J.
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Abstract

Aberrantly expressed lysine methyltransferases G9a and GLP, which catalyze mono- and di-methylation of histone H3 lysine 9 (H3K9), have been implicated in numerous cancers. Recent studies have uncovered both catalytic and non-catalytic 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, 10 (MS8709), as a potential anticancer therapeutic. 10 induces G9a/GLP degradation in a concentration-, time, and ubiquitin-proteasome system (UPS)-dependent manner, does not alter the mRNA expression of G9a/GLP and is selective for G9a/GLP over other methyltransferases. Moreover, 10 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, 10 is a valuable chemical biology tool to further investigate the functions of G9a/GLP and a potential therapeutic for treating G9a/GLP-dependent cancers. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/582210v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@1b3c923org.highwire.dtl.DTLVardef@5a22f0org.highwire.dtl.DTLVardef@1abbabeorg.highwire.dtl.DTLVardef@1711f29_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Velez, J., Han, Y., Yim, H., Yang, P., Deng, Z., Park, K., Kabir, M., Kaniskan, H., Xiong, Y., Jin, J.. 2024-02-29. Discovery of the First-in-class G9a/GLP PROTAC Degrader. https://doi.org/10.1101/2024.02.26.582210

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