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LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation
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Journal Article
LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation
2025
Overview
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
LY
sosome
M
embrane
TA
rgeting
C
himera
s
(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 KRAS
G12D
signaling can be potently inhibited by LYMTACs. Mechanistically, LYMTACs display multi-pharmacology and exert their activity through both target relocalization into the lysosome and degradation. We further generalize LYMTACs across various LMPs and thus offer a platform to access challenging membrane proteins through targeted protein relocalization and degradation.
LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/109
/ 14
/ 14/19
/ 82/29
/ 82/58
/ Animals
/ Chimeras
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Ligands
/ Membrane Proteins - metabolism
/ Protein Kinase Inhibitors - chemistry
/ Protein Kinase Inhibitors - pharmacology
/ Protein Transport - drug effects
/ Proteins
/ Science
/ Signal Transduction - drug effects
/ Small Molecule Libraries - chemistry
