Group-Transfer Chimeras for Induced Proximity (GRIPs)
Induced proximity is more than ubiquitination and targeted protein degradation.
In the recent literature we have seen proximity-inducing modalities for phosphorylation and dephosphorylation, deubiquitination, glycosylation and more.
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However, when we induce proximity between our protein of interest (POI) and an effector protein, it can be counterproductive to use inhibitory ligands for recruitment of the effector, as we need to keep it active to do its job.
This limits us to non-inhibitory binders, which exist for less than 1% of all writers/erasers.
Unless we take advantage of the newly developed strategy introducing GRIPs! ๐ก
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This strategy converts enzyme inhibitors into proximity-inducing chimeras via a cleavable group-transfer handle that covalently appends a POI binder onto a Cys or Lys on the effector, releasing the inhibitor from the active site.
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42 group-transfer handles with distinct reactivity targeting Cys and Lys
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~5,000 plausible inhibitor-residue pairs from PDB mining and chemoproteomics
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6 GRIPs classes: writers or erasers of 3 PTMs (O-GlcNAc, Ser/Thr and Tyr phosphorylation)
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16 effector-POI pairs validated
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4 fully endogenous systems
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Compatible with covalent/non-covalent, active-site/allosteric inhibitors
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๐ธ Baricitinib-based GRIP removed JAK2 rebound signaling in a myeloproliferative neoplasm model (superior to inhibition)
๐ธ STAT3-targeting GRIP achieved >4x higher potency than an occupancy-driven inhibitor
๐ธ Gefitinib-based GRIPs provided more persistent EGFR inhibition vs. an occupancy-based control
๐ธ Osimertinib-derived GRIPs activated EGFR, mimicking EGF, and selectively killed KRAS-mutant cells while sparing wild-type
๐ธ AKT-recruiting GRIPs induced Liprin condensate formation with fewer off-targets vs. AMPK-activator chimera
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๐ธ Since the reactive warhead undergoes 1,4-addition/elimination sequence, the authors tuned its reactivity by modulating the quality of the leaving group (N to O/S swap, electron-withdrawing groups), which resulted in 6-100x increased reactivity.
๐ธ For lysine, they developed SuFA (electrophilic functional group) with ~5x improved stability over NASA. Global proteomics confirmed high specificity of both group transfer and PTM editing.
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What I would like to highlight is that this strategy allows covalent modification of proteins in fully endogenous biological systems while leveraging vast pool of available small molecule ligands.
๐ง What do you think about this strategy to overcome the scalability bottleneck?
Preprint: https://lnkd.in/gkFQiaBf
Leave your comment under my LinkedIn post here.
