Discovery of a first-in-class EZH2 selective degrader.
Animals
Antineoplastic Agents
/ chemistry
Cell Death
/ drug effects
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Female
Gene Knockout Techniques
Humans
Hydrophobic and Hydrophilic Interactions
Male
Mice
Mice, Inbred BALB C
Molecular Targeted Therapy
Piperazines
/ pharmacology
Proteolysis
/ drug effects
Pyridines
/ pharmacology
Triple Negative Breast Neoplasms
/ drug therapy
Unfolded Protein Response
/ drug effects
Xenograft Model Antitumor Assays
Journal
Nature chemical biology
ISSN: 1552-4469
Titre abrégé: Nat Chem Biol
Pays: United States
ID NLM: 101231976
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
09
05
2019
accepted:
27
10
2019
pubmed:
11
12
2019
medline:
28
4
2020
entrez:
11
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31819273
doi: 10.1038/s41589-019-0421-4
pii: 10.1038/s41589-019-0421-4
pmc: PMC6982609
mid: NIHMS1063537
doi:
Substances chimiques
Antineoplastic Agents
0
Piperazines
0
Pyridines
0
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
214-222Subventions
Organisme : NCI NIH HHS
ID : R01 CA218600
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA220491
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA078207
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA230854
Pays : United States
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States
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