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Discovery of a first-in-class EZH2 selective degrader.
- Source :
-
Nature chemical biology [Nat Chem Biol] 2020 Feb; Vol. 16 (2), pp. 214-222. Date of Electronic Publication: 2019 Dec 09. - Publication Year :
- 2020
-
Abstract
- 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.
- Subjects :
- Animals
Antineoplastic Agents pharmacokinetics
Cell Death drug effects
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors
Enhancer of Zeste Homolog 2 Protein genetics
Female
Gene Knockout Techniques
Humans
Hydrophobic and Hydrophilic Interactions
Male
Mice
Mice, Inbred BALB C
Molecular Targeted Therapy
Proteolysis drug effects
Triple Negative Breast Neoplasms drug therapy
Triple Negative Breast Neoplasms metabolism
Unfolded Protein Response drug effects
Xenograft Model Antitumor Assays
Antineoplastic Agents chemistry
Antineoplastic Agents pharmacology
Enhancer of Zeste Homolog 2 Protein metabolism
Piperazines pharmacology
Pyridines pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1552-4469
- Volume :
- 16
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Nature chemical biology
- Publication Type :
- Academic Journal
- Accession number :
- 31819273
- Full Text :
- https://doi.org/10.1038/s41589-019-0421-4