LYMTACs:chimeric small molecules repurpose lysosomal membrane proteins for target protein relocalization and degradation
Dhanusha A. Nalawansha, Georgios Mazis, Gitte Husemoen, Kate S. Ashton, Weixian Deng, Ryan P. Wurz, Anh Tran, Brian A. Lanman, Jiansong Xie, Robert G. Guenette, Shiqian Li, Christopher E. Smith, Suresh Archunan, Manoj K. Agnihotram, Arghya Sadhukhan, Rajiv Kapoor, Chris Wilde, Sajjan Koirala, Felipe de Sousa e Melo, Patrick Ryan Potts
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 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.