The enhancer of zeste homolog 2 (EZH2) is the main enzymatic subunit of the PRC2 complex, which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) to promote transcriptional silencing. EZH2 is overexpressed in multiple types of cancer including triple-negative breast cancer (TNBC), and high expression levels correlate with poor prognosis. Several EZH2 inhibitors, which inhibit the methyltransferase activity of EZH2, have shown promise in treating sarcoma and follicular lymphoma in clinics. However, EZH2 inhibitors are ineffective at blocking proliferation of TNBC cells, even though they effectively reduce the H3K27me3 mark. Using a hydrophobic tagging approach, we generated MS1943, a first-in-class EZH2 selective degrader that effectively reduces EZH2 levels in cells. Importantly, MS1943 has a profound cytotoxic effect in multiple TNBC cells, while sparing normal cells, and is efficacious in vivo, suggesting that pharmacologic degradation of EZH2 can be advantageous for treating the cancers that are dependent on EZH2.
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The scripts used to analyze RNA-seq data and to produce some of the plots are available at https://github.com/parsonslabmssm/MS1943.
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This work was supported in part by grant no. R01CA230854 (to J.J. and R.P.) from the US National Institutes of Health. J.J. also acknowledges the support by grant no. R01CA218600 from the US National Institutes of Health and an endowed professorship by the Icahn School of Medicine at Mount Sinai. B.D. acknowledges support by the Medical Scientist Training Program (MSTP) training grant no. T32GM007280 at the Icahn School of Mount Sinai from the US National Institutes of Health. We thank the National Institute of Mental Health Psychoactive Drug Screening Program (NIMH-PDSP) for generating the selectivity data of MS1943 over GPCRs, ion channels and transporters. We also thank C. Lee (Icahn School of Medicine at Mount Sinai) and W. Ma (Memorial Sloan Kettering Cancer Center) for providing reagents for shRNA knockdown experiments. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. Research reported in this paper was supported by the Office of Research Infrastructure of the US National Institutes of Health under award no. S10OD018522. The content is solely the responsibility of the authors and does not necessarily represent the official views of the US National Institutes of Health.
J.J., R.P., A.M., E.S. and X.Y. are inventors for a patent application filed by the Icahn School of Medicine at Mount Sinai. J.J. is an equity shareholder and consultant of Cullgen.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Figs. 1–22, Tables 1–3 and Supplementary Note.
Time-lapse pictures of MDA-MB-468 cells treated with DMSO. Cells were treated with DMSO for 3 days.
Time-lapse pictures of MDA-MB-468 cells treated with C24. Cells were treated with C24 (4 µM) for 3 days.
Time-lapse pictures of MDA-MB-468 cells treated with MS1943. Cells were treated with MS1943 (4 µM) for 3 d.
Time-lapse pictures of HCC1187 cells treated with DMSO. Cells were treated with DMSO for 3 d.
Time-lapse pictures of HCC1187 cells treated with C24. Cells were treated with C24 (4 µM) for 3 d.
Time-lapse pictures of HCC1187 cells treated with MS1943. Cells were treated with MS1943 (4 µM) for 3 d.
Time-lapse pictures of HCC70 cells treated with DMSO. Cells were treated with DMSO for 3 d.
Time-lapse pictures of HCC70 cells treated with C24. Cells were treated with C24 (4 µM) for 3 d.
Time-lapse pictures of HCC70 cells treated with MS1943. Cells were treated with MS1943 (4 µM) for 3 d.
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Ma, A., Stratikopoulos, E., Park, K. et al. Discovery of a first-in-class EZH2 selective degrader. Nat Chem Biol 16, 214–222 (2020). https://doi.org/10.1038/s41589-019-0421-4