biostudies-literatureUnknown16(1)Nalawansha DAProximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRASG12DNature communications7812https://www.ebi.ac.uk/biostudies/studies/S-EPMC12370906biostudies-literatureLYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.PMC12370906Lanman BAHusemoen GSadhukhan AGuenette RGKapoor RDe Sousa E Melo FNalawansha DAArchunan SKoirala SLi STran ATWilde CPotts PRXie JSmith CEMazis GAgnihotram MKAshton KSWurz RPDeng WfalseLYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LYsosome Membrane TArgeting Chimeras (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRASG12D2025-01-01T00:00:00Z2025 Aug2026-05-08T10:44:06.509Z2026-04-07T23:47:02.296ZS-EPMC123709064084136810.1038/s41467-025-63128-4