Abstract A055: Discovery of a novel, highly potent VHL-recruiting EZH2 PROTAC degrader targeting MLL-r AML

Abstract

Abstract Mutated or overexpressed Enhancer of Zeste Homolog 2 (EZH2), the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), has been implicated in numerous cancers, including breast, leukemia, and lung. Through its methyltransferase activity, EZH2 tri-methylates H3K27 to repress transcription. In addition to its enzymatic activity, recent studies have highlighted non-enzymatic oncogenic functions of EZH2 that limit the efficacy of enzymatic inhibitors. Therefore, alternative therapeutic strategies such as proteolysis targeting chimera (PROTAC) degraders that suppress both enzymatic and non-enzymatic activity have been developed. PROTACs are heterobifunctional molecules consisting of a protein of interest (POI) binder linked to an E3-ligase ligand. The manufactured proximity between the POI and the recruited E3-ligase complex initiates ubiquitination of the POI, resulting in its degradation via the 26S proteasome. EZH2 exhibits enzymatic and non-enzymatic oncogenic activity in various cancers including MLL1-rearranged acute myeloid leukemia (MLL-r AML) and triple negative breast cancer (TNBC). Here we present MS8847, a novel VHL-recruiting EZH2 PROTAC degrader. In MLL-r AML cells, MS8847 induces potent EZH2 degradation in a ubiquitin proteasome-, time- and concentration-dependent manner. Compared to the previously published EZH2-targeting PROTAC degraders (MS8815, YM281, U3i, and E7) and parent inhibitor, Tazemetostat, MS8847 displays superior EZH2 degradation and cell growth inhibition in MLL-r AML cell lines dependent on both enzymatic and non-enzymatic EZH2 activity. MS8847 also induces EZH2 degradation and cell growth inhibition in TNBC cell lines. Moreover, MS8847 has a favorable PK profile making it suitable for in vivo studies. Together, MS8847 offers an improved VHL-recruiting EZH2 PROTAC degrader with potential as an effective therapeutic agent to treat EZH2-dependent cancers. Citation Format: Julia Velez, Xufen Yu, Brandon Dale, Kwang-Su Park, H. Ümit Kaniskan, Jian Jin. Discovery of a novel, highly potent VHL-recruiting EZH2 PROTAC degrader targeting MLL-r AML [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A055.