Dataset Information

Discovery of a first-in-class EZH2 selective degrader.

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.

SUBMITTER: Ma A

PROVIDER: S-EPMC6982609 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Discovery of a first-in-class EZH2 selective degrader.

Ma Anqi A Stratikopoulos Elias E Park Kwang-Su KS Wei Jieli J Martin Tiphaine C TC Yang Xiaobao X Schwarz Megan M Leshchenko Violetta V Rialdi Alexander A Dale Brandon B Lagana Alessandro A Guccione Ernesto E Parekh Samir S Parsons Ramon R Jin Jian J

Nature chemical biology 20191209 2

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 clini ...[more]

PMID: 31819273

Dataset Information

Discovery of a first-in-class EZH2 selective degrader.

Publications

Discovery of a first-in-class EZH2 selective degrader.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Similar Datasets

Discovery and resistance mechanism of a selective CDK12 degrader.
| S-EPMC8590456 | biostudies-literature

Discovery of the first-in-class potent and isoform-selective human carbonic anhydrase III inhibitors.
| S-EPMC10128460 | biostudies-literature

Discovery of a Highly Potent and Selective HDAC3 and HDAC8 PROTAC Dual Degrader
2023-07-18 | GSE211758 | GEO

Discovery of the first potent proteolysis targeting chimera (PROTAC) degrader of indoleamine 2,3-dioxygenase 1.
| S-EPMC7606109 | biostudies-literature

Discovery of a first-in-class reversible DNMT1-selective inhibitor with improved tolerability and efficacy in acute myeloid leukemia
| S-EPMC8594913 | biostudies-literature

Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu<sub>7</sub> Positive Allosteric Modulator Tool Compound.
| S-EPMC7488291 | biostudies-literature

Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression.
| S-EPMC6545112 | biostudies-literature

Discovery and clinical introduction of first-in-class imipridone ONC201.
| S-EPMC5342060 | biostudies-literature

First-in-Class Selective Inhibitors of the Lysine Acetyltransferase KAT8.
| S-EPMC10226132 | biostudies-literature

Discovery of First-in-Class Protein Arginine Methyltransferase 5 (PRMT5) Degraders.
| S-EPMC7486226 | biostudies-literature