biostudies-literatureShao QMark Foundation For Cancer ResearchApple Tree PartnersNational Cancer InstituteNCI NIH HHSNIH HHS24788-24799https://www.ebi.ac.uk/biostudies/studies/S-EPMC12011284biostudies-literatureUnknown146(36)14-3-3 proteins have a unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that interactions of 14-3-3 with specific phosphorylated substrate proteins can be enhanced through small-molecule natural products or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates and potential neo-substrates to sequester and inhibit their function remains elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has cysteine C38 at the substrate-binding interface, near the sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screen a fully synthetic cysteine-reactive covalent ligJournal of the American Chemical SocietyTargeted Protein Localization by Covalent 14-3-3 Recruitment.PMC12011284S10 OD024998R35 CA263814R35CA263814Nomura DKDuong TNPark IOrr LMShao QfalseTargeted Protein Localization by Covalent 14-3-3 Recruitment.14-3-3 proteins have a unique ability to bind and sequester a multitude of diverse phosphorylated signaling proteins and transcription factors. Many previous studies have shown that interactions of 14-3-3 with specific phosphorylated substrate proteins can be enhanced through small-molecule natural products or fully synthetic molecular glue interactions. However, enhancing 14-3-3 interactions with both therapeutically intractable transcription factor substrates and potential neo-substrates to sequester and inhibit their function remains elusive. One of the 14-3-3 proteins, 14-3-3σ or SFN, has cysteine C38 at the substrate-binding interface, near the sites where previous 14-3-3 molecular glues have been found to bind. In this study, we screen a fully synthetic cysteine-reactive covalent lig2024-01-01T00:00:00Z2024 Sep2026-06-02T04:15:02.79Z2025-07-03T03:04:51.729ZS-EPMC120112843919654510.1021/jacs.3c12389