biostudies-literatureSwartzel JCAmerican Cancer SocietyJapan Agency for Medical Research and DevelopmentNational Cancer InstituteNCI NIH HHSNIGMS NIH HHSJapan Society for the Promotion of Science1789-1798https://www.ebi.ac.uk/biostudies/studies/S-EPMC10367122biostudies-literatureUnknown17(7)The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and susACS chemical biologyTargeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.PMC1036712218063889R35CA197589F31 CA232477R35 CA19758920H05699T32 GM067543F31CA232477Carder EJDaftary MMaeda TSwartzel JCCrews CMBond MJZimmer JTPintado-Urbanc APDouglas TKrone MWSimon MDfalseTargeted Degradation of mRNA Decapping Enzyme DcpS by a VHL-Recruiting PROTAC.The RNA decapping scavenger protein, DcpS, has recently been identified as a dependency in acute myeloid leukemia (AML). The potent DcpS inhibitor RG3039 attenuates AML cell viability, and shRNA knockdown of DcpS is also antiproliferative. Importantly, DcpS was found to be non-essential in normal human hematopoietic cells, which opens a therapeutic window for AML treatment by DcpS modulation. Considering this strong DcpS dependence in AML cell lines, we explored PROTAC-mediated degradation as an alternative strategy to modulate DcpS activity. Herein, we report the development of JCS-1, a PROTAC exhibiting effective degradation of DcpS at nanomolar concentrations. JCS-1 non-covalently binds DcpS with a RG3039-based warhead and recruits the E3 ligase VHL, which induces potent, rapid, and sus2022-01-01T00:00:00Z2022 Jul2026-04-12T23:14:40.967Z2025-02-19T01:18:09.172ZS-EPMC103671223574947010.1021/acschembio.2c00145