LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation.

ABSTRACT: 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 KRASG12D

SUBMITTER: Nalawansha DA 

PROVIDER: S-EPMC12370906 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature