A Scalable Design for Proximity-Inducing Molecules
Year: 2026
Type: preprint
Abstract: Chimeric molecules, which bring together an effector enzyme and a protein-of-interest (POI) to add/remove post-translational modifications (PTMs), are furnishing transformative modalities (e.g., PROTACs). However, these chimeras’ scalability is limited as they employ rare, non-inhibitory binders of effectors. We report GRoup-transfer chimeras for Inducing Proximity (GRIPs) that employ abundantly available effectors’ inhibitors to append POI binder on the effector using group-transfer handles. To demonstrate scalability, we develop 6 GRIPs classes for 3 PTMs utilizing diverse inhibitor, spanning 16 effector‒POI pairs. Furthermore, we report a toolbox of 42 tunable group-transfer handles for Cys/Lys residues and ∼5000 inhibitor‒residue pairs for diverse effectors. Using global proteomics, we confirm the specificity for group transfer and PTM editing. GRIPs endowed new functionalities to POI drugs, including preventing rebound signaling upon drug withdrawal, a more potent/persistent inhibition, and inhibitor-induced pathway activation in 4 fully-endogenous systems. In diverse hemi -endogenous systems (tagged POI), GRIPs induced condensate formation with reduced off-targets, cleared pathogenic PTMs, and initiated PTM crosstalk. Overall, GRIPs provide a scalable and versatile platform for PTM editing. Graphical abstract
Authors: Endri Karaj, Varsha Venkatarangan, Shaimaa H. Sindi, Surached Siriwongsup, Chaiheon Lee, Rajaiah Pergu, Vedagopuram Sreekanth, Karishma Kailass, Kien Tran, Prashant Singh, Sameek Singh, Junya Kawai, Jeffrey E. Fung, Mahilet Tefera, Rohil Dhaliwal, Santosh K. Chaudhary, April Keyes, Ananthan Sadagopan, Lisa Boatner, Neel H. Shah, Charlie Fehl, Keriann M. Backus, Amit Choudhary
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Chemical approaches for precision genome editing, G5735907136, G6051350543, Probing tyrosine phosphatase structure and function, Development of phosphorylation-inducing chimeric small molecules, UCLA SPORE in Brain Cancer, Development of phosphorylation editing chimeras using kinase inhibitors, Development of platforms for beta cell-specific delivery and ligand discovery, Induced-Proximity Platform to Control Cellular Signaling and Proteostasis
OpenAlex ID: W7130949951