{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Velez J"],"funding":["National Cancer Institute","NCI NIH HHS","National Institutes of Health","NIH HHS","Icahn School of Medicine at Mount Sinai","NIGMS NIH HHS"],"pagination":["116154"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10901292"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["267"],"pubmed_abstract":["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."],"journal":["European journal of medicinal chemistry"],"pubmed_title":["Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2."],"pmcid":["PMC10901292"],"funding_grant_id":["3R01CA230854S1","R01CA230854","1S10OD025132","1S10OD028504","T32CA078207","R01 CA218600","T32GM007280","R01 CA230854","R01CA268519","3R01CA218600-05S1","S10 OD025132","R01 CA268519","T32 CA078207","T32 GM146636","T32 GM007280","S10 OD028504"],"pubmed_authors":["Kaniskan HU","Dale B","Jin J","Park KS","Yu X","Velez J"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of a novel, highly potent EZH2 PROTAC degrader for targeting non-canonical oncogenic functions of EZH2.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-06-27T03:19:33.508Z","creation":"2025-04-04T19:27:25.419Z"},"accession":"S-EPMC10901292","cross_references":{"pubmed":["38295690"],"doi":["10.1016/j.ejmech.2024.116154"]}}