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 T. 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 and Patrick Ryan Potts ()
Additional contact information
Dhanusha A. Nalawansha: Amgen Research
Georgios Mazis: Ronnegade 8
Gitte Husemoen: Ronnegade 8
Kate S. Ashton: Amgen Research
Weixian Deng: Amgen Research
Ryan P. Wurz: Amgen Research
Anh T. Tran: Amgen Research
Brian A. Lanman: Amgen Research
Jiansong Xie: Amgen Research
Robert G. Guenette: Amgen Research
Shiqian Li: Amgen Research
Christopher E. Smith: Amgen Research
Suresh Archunan: Syngene Amgen Research & Development Center
Manoj K. Agnihotram: Syngene Amgen Research & Development Center
Arghya Sadhukhan: Syngene Amgen Research & Development Center
Rajiv Kapoor: Syngene Amgen Research & Development Center
Chris Wilde: Amgen Research
Sajjan Koirala: Amgen Research
Felipe De Sousa E Melo: Amgen Research
Patrick Ryan Potts: Amgen Research

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-63128-4

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