Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation
Abstract
PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered "undruggable". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.
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BibTeX
@article{michon2026synthesis,
title = {{Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation}},
author = {Marine Michon and Sebastien Curpanen and Ombeline Pessey and Robert Thai and Jean-Charles Gaillard and Gaëtan Herbette and Karen Hinsinger and Daniel Gillet and Jean Armengaud and Jean-Christophe Cintrat and Julien Barbier},
journal = {European Journal of Medicinal Chemistry},
year = {2026},
month = oct,
doi = {10.1016/j.ejmech.2026.118645},
url = {https://hal.science/hal-05787649v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Synthesis and biological evaluation of Retro-2-based PROTACs reveal PEG-linker length and warhead impact on GSPT1 degradation
AU - Marine Michon
AU - Sebastien Curpanen
AU - Ombeline Pessey
AU - Robert Thai
AU - Jean-Charles Gaillard
AU - Gaëtan Herbette
AU - Karen Hinsinger
AU - Daniel Gillet
AU - Jean Armengaud
AU - Jean-Christophe Cintrat
AU - Julien Barbier
PY - 2026
DA - 2026/10/13
JO - European Journal of Medicinal Chemistry
DO - 10.1016/j.ejmech.2026.118645
UR - https://hal.science/hal-05787649v1
AB - PROteolysis TArgeting Chimeras are attracting growing interest in pharmaceutical research thanks to their catalytic and irreversible mechanism, which is capable of targeting proteins previously considered "undruggable". These bifunctional molecules hijack the cellular ubiquitin-proteasome system by recruiting E3 ligases (such as CRBN or VHL) to induce the selective degradation of a target protein. Their efficacy has been demonstrated against various disorders and several compounds have reached phase I-III clinical trials, reinforcing their appeal. In the fight against toxins, derivatives of the Retro-2 molecule (active against Shigatoxins, ricin, and various pathogens) have been developed. These molecules act on host cells by disrupting the intracellular trafficking of pathogens, targeting in particular the Sec16A and/or ASNA1 proteins. Our study presents the synthesis and characterization of new chemical probes based on PROTAC technology, combining a CRBN ligand derived from thalidomide, a Retro-2 derivative, and variable-length PEG chain linkers to better understand the mechanism of action of Retro-2-derived molecules. Contrary to initial assumptions, our results do not show proteasome-dependent degradation of the protein targets, but demonstrate that PEG-2 molecules can degrade the translation termination factor GSPT1 despite the normally propitious anchoring of the PEG linker at position 4 of the phthalimide ring. Furthermore, this study shows for the first time that GSPT1 degradation depends on the length of the flexible PEG chain linker.
SN - 0223-5234
SN - 1768-3254
ER -