Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed in triple-negative breast cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic inhibitors are ineffective in suppressing the growth of TNBC cells that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation of these cells, suggesting that EZH2 protein overexpression but not its catalytic activity is critical for driving TNBC progression. Several proteolysis targeting chimera (PROTAC) degraders of EZH2, including the von Hippel−Lindau (VHL)-recruiting PROTAC YM281, have been reported. However, the effects of these EZH2 PROTACs in TNBC cells were not investigated. Here, we report the discovery and characterization of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-, time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC cell lines and primary patient TNBC cells.
EZH2 (enhancer of zeste homolog 2) is the main catalytic subunit of the polycomb repressive complex 2 (PRC2) that catalyzes methylation of histone H3K27. EZH2 is overexpressed in a broad spectrum of cancers including prostate, myeloma and lymphoma, and high expression correlates with poor prognosis. However, EZH2 inhibitors, which do not affect EZH2 protein levels, are ineffective at inhibiting growth of TNBC and other breast cancer cell lines with EZH2 overexpression even though they effectively inhibit the catalytic activity of EZH2/PRC2. It has also been shown that overexpression of EZH2 is a major driver for breast cancer development and progression, and knockdown of EZH2 inhibits proliferation of TNBC and other breast cancer cells. These results together suggest that EZH2 overexpression, but not the methyltransferase activity of EZH2, is critical for driving breast cancer progression. Bivalent inhibitor technologies such as PROTACs (proteolysis targeting chimeras) and hydrophobic tagging have been successfully applied to selective degradation of multiple protein targets. CRBN-recruiting (E7) and VHL-recruiting EZH2 (YM281) EZH2 targeting PROTACs have been reported, but do not show potent efficacy in targeting TNBC. Here, we characterize MS8815, a VHL-recruiting EZH2 degrader, that we created. MS8815 displayed nanomolar efficacy at EZH2 degradation and potent in vitro effects on TNBC cell lines, no off-target interactions and utilized the canonical PROTAC mechanism of action. Based on these promising preliminary results, we report MS8815 as the best-in-class EZH2 PROTAC degrader that is able to efficiently degrade EZH2 and kill TNBC cells. Citation Format: Brandon Dale, Chris Anderson, Kwang-su Park, H. Ümit Kaniskan, Xufen Yu, Jian Jin. Targeting triple negative breast cancer with a VHL recruiting EZH2 protein degrader [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2922.
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