Abstract 4511: Discovery of the first-in-class G9a/GLP PROTAC degrader

Abstract

Abstract G9a and GLP are lysine methyltransferases that catalyze dimethylation of histone H3 lysine 9 (H3K9me2), a transcriptionally repressive mark. Aberrantly expressed G9a/GLP has been implicated in numerous cancers, including prostate, lung, and leukemia. The oncogenic activity of G9a/GLP is attributed to both its catalytic and non-catalytic functions, such as forming co-activator complexes with p300, CARM1, GRIP1, and Mediator to positively regulate gene transcription. As such, current G9a/GLP enzymatic inhibitors display limited anti-cancer activity. As an alternative therapeutic strategy, PROTAC degraders harness the ubiquitin-proteasome system (UPS) to effectively eliminate oncoproteins and abrogate all catalytic and non-catalytic functions. Here, we present the first-in-class G9a/GLP PROTAC degrader, MS8709, which potently degrades G9a and GLP in a time-, concentration-, and UPS-dependent manner. Moreover, MS8709 induces superior cell growth inhibition compared to its parent inhibitor in prostate, lung, and leukemia cell lines. Overall, MS8709 is a useful chemical tool to investigate G9a/GLP biology and offers a novel approach for the treatment of G9a/GLP-dependent cancers. Citation Format: Julia Velez, Yulin Han, Kwang-Su Park, Md Kabir, Peiyi Yang, Yan Xiong, H. Umit Kaniskan, Jian Jin. Discovery of the first-in-class G9a/GLP PROTAC degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4511.