Discovery of a first-in-class EZH2 selective degrader
Anqi Ma # 1, Elias Stratikopoulos # 2, Kwang-Su Park # 1, Jieli Wei 1, Tiphaine C Martin 2, Xiaobao Yang 1, Megan Schwarz 2, Violetta Leshchenko 3, Alexander Rialdi 2, Brandon Dale 1, Alessandro Lagana 4, Ernesto Guccione 1 2, Samir Parekh 2 3, Ramon Parsons 5, Jian Jin 6 7
The enhancer of zeste homolog 2 (EZH2) may be the primary enzymatic subunit from the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to advertise transcriptional silencing. EZH2 is overexpressed in multiple kinds of cancer including triple-negative cancer of the breast (TNBC), and expression levels correlate with poor prognosis. Several EZH2 inhibitors, which hinder the methyltransferase activity of EZH2, have proven promise for sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, while they effectively lessen the H3K27me3 mark. Utilizing a hydrophobic tagging approach, we generated MS1943, an initial-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 includes a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and it is effective in vivo, suggesting that pharmacologic degradation of EZH2 could be beneficial for the treatment of the cancers which are determined by EZH2.

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