biostudies-literatureVelez JNational Cancer InstituteNCI NIH HHSNational Institutes of HealthNIH HHSIcahn School of Medicine at Mount SinaiNIGMS NIH HHS116154https://www.ebi.ac.uk/biostudies/studies/S-EPMC10901292biostudies-literatureUnknown267Aberrant expression of EZH2, the main catalytic subunit of PRC2, has been implicated in numerous cancers, including leukemia, breast, and prostate. Recent studies have highlighted non-catalytic oncogenic functions of EZH2, which EZH2 catalytic inhibitors cannot attenuate. Therefore, proteolysis-targeting chimera (PROTAC) degraders have been explored as an alternative therapeutic approach to suppress both canonical and non-canonical oncogenic activity. Here we present MS8847, a novel, highly potent EZH2 PROTAC degrader that recruits the E3 ligase von Hippel-Lindau (VHL). MS8847 degrades EZH2 in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Notably, MS8847 induces superior EZH2 degradation and anti-proliferative effects in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells compared to previously published EZH2 PROTAC degraders. Moreover, MS8847 degrades EZH2 and inhibits cell growth in triple-negative breast cancer (TNBC) cell lines, displays efficacy in a 3D TNBC in vitro model, and has a pharmacokinetic (PK) profile suitable for in vivo efficacy studies. Overall, MS8847 is a valuable chemical tool for the biomedical community to investigate canonical and non-canonical oncogenic functions of EZH2.European journal of medicinal chemistryDiscovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.PMC109012923R01CA230854S1R01CA2308541S10OD0251321S10OD028504T32CA078207R01 CA218600T32GM007280R01 CA230854R01CA2685193R01CA218600-05S1S10 OD025132R01 CA268519T32 CA078207T32 GM146636T32 GM007280S10 OD028504Kaniskan HUDale BJin JPark KSYu XVelez JfalseDiscovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.Aberrant expression of EZH2, the main catalytic subunit of PRC2, has been implicated in numerous cancers, including leukemia, breast, and prostate. Recent studies have highlighted non-catalytic oncogenic functions of EZH2, which EZH2 catalytic inhibitors cannot attenuate. Therefore, proteolysis-targeting chimera (PROTAC) degraders have been explored as an alternative therapeutic approach to suppress both canonical and non-canonical oncogenic activity. Here we present MS8847, a novel, highly potent EZH2 PROTAC degrader that recruits the E3 ligase von Hippel-Lindau (VHL). MS8847 degrades EZH2 in a concentration-, time-, and ubiquitin-proteasome system (UPS)-dependent manner. Notably, MS8847 induces superior EZH2 degradation and anti-proliferative effects in MLL-rearranged (MLL-r) acute myeloid leukemia (AML) cells compared to previously published EZH2 PROTAC degraders. Moreover, MS8847 degrades EZH2 and inhibits cell growth in triple-negative breast cancer (TNBC) cell lines, displays efficacy in a 3D TNBC in vitro model, and has a pharmacokinetic (PK) profile suitable for in vivo efficacy studies. Overall, MS8847 is a valuable chemical tool for the biomedical community to investigate canonical and non-canonical oncogenic functions of EZH2.2024-01-01T00:00:00Z2024 Mar2026-06-27T03:19:33.508Z2025-04-04T19:27:25.419ZS-EPMC109012923829569010.1016/j.ejmech.2024.116154