TY - JOUR
T1 - Targeting Triple-Negative Breast Cancer by a Novel Proteolysis Targeting Chimera Degrader of Enhancer of Zeste Homolog 2
AU - Dale, Brandon
AU - Anderson, Chris
AU - Park, Kwang Su
AU - Kaniskan, H. Ümit
AU - Ma, Anqi
AU - Shen, Yudao
AU - Zhang, Chengwei
AU - Xie, Ling
AU - Chen, Xian
AU - Yu, Xufen
AU - Jin, Jian
N1 - Funding Information:
This research was supported in part by the grants R01CA230854 (to J.J.), R01CA218600 (to J.J.), and R01CA268519 (to J.J.) from the National Cancer Institute (NCI) at the U.S. National Institutes of Health. J.J. acknowledges the support by an endowed professorship by the Icahn School of Medicine at Mount Sinai. This work utilized the NMR Spectrometer Systems at Mount Sinai acquired with funding from National Institutes of Health SIG grants 1S10OD025132 and 1S10OD028504. B.D. acknowledges support from the Medical Scientist Training Program (training grant T32GM007280) at the Icahn School of Medicine at Mount Sinai and the grant (3R01CA230854S1) from the U.S. National Institutes of Health. We thank Dr. Pamela Cheung at the Cancer Cell Organoid Core (CCOC) at Mount Sinai for providing patient primary cell line 515a.
Publisher Copyright:
© 2022 American Chemical Society.
PY - 2022/7/8
Y1 - 2022/7/8
N2 - Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed in triple-negative breast cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic inhibitors are ineffective in suppressing the growth of TNBC cells that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation of these cells, suggesting that EZH2 protein overexpression but not its catalytic activity is critical for driving TNBC progression. Several proteolysis targeting chimera (PROTAC) degraders of EZH2, including the von Hippel-Lindau (VHL)-recruiting PROTAC YM281, have been reported. However, the effects of these EZH2 PROTACs in TNBC cells were not investigated. Here, we report the discovery and characterization of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-, time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC cell lines and primary patient TNBC cells.
AB - Enhancer of zeste homolog 2 (EZH2), a catalytic subunit of polycomb repressive complex 2 (PRC2), is overexpressed in triple-negative breast cancer (TNBC), correlating with poor prognosis. However, EZH2 catalytic inhibitors are ineffective in suppressing the growth of TNBC cells that are dependent on EZH2. Knockdown of EZH2 inhibits the proliferation of these cells, suggesting that EZH2 protein overexpression but not its catalytic activity is critical for driving TNBC progression. Several proteolysis targeting chimera (PROTAC) degraders of EZH2, including the von Hippel-Lindau (VHL)-recruiting PROTAC YM281, have been reported. However, the effects of these EZH2 PROTACs in TNBC cells were not investigated. Here, we report the discovery and characterization of a novel, potent, and selective EZH2 PROTAC degrader, MS8815 (compound 16), which induced robust EZH2 degradation in a concentration-, time-, and proteasome-dependent manner in TNBC cells. Importantly, 16 effectively suppressed the cell growth in multiple TNBC cell lines and primary patient TNBC cells.
KW - EZH2
KW - PROTAC
KW - cancer treatment
KW - epigenetics
KW - triple-negative breast cancer
UR - http://www.scopus.com/inward/record.url?scp=85135071089&partnerID=8YFLogxK
U2 - 10.1021/acsptsci.2c00100
DO - 10.1021/acsptsci.2c00100
M3 - Article
AN - SCOPUS:85135071089
VL - 5
SP - 491
EP - 507
JO - ACS Pharmacology and Translational Science
JF - ACS Pharmacology and Translational Science
SN - 2575-9108
IS - 7
ER -