TY - JOUR
T1 - Discovery of a first-in-class EZH2 selective degrader
AU - Ma, Anqi
AU - Stratikopoulos, Elias
AU - Park, Kwang Su
AU - Wei, Jieli
AU - Martin, Tiphaine C.
AU - Yang, Xiaobao
AU - Schwarz, Megan
AU - Leshchenko, Violetta
AU - Rialdi, Alexander
AU - Dale, Brandon
AU - Lagana, Alessandro
AU - Guccione, Ernesto
AU - Parekh, Samir
AU - Parsons, Ramon
AU - Jin, Jian
N1 - Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85076345170&partnerID=8YFLogxK
U2 - 10.1038/s41589-019-0421-4
DO - 10.1038/s41589-019-0421-4
M3 - Article
C2 - 31819273
AN - SCOPUS:85076345170
SN - 1552-4450
VL - 16
SP - 214
EP - 222
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 2
ER -