Exploring Non-Covalent Pin1-PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line.
- 1CNRS, BioCIS, CY Cergy Paris Université, Cergy Pontoise, France.
- 2CNRS, BioCIS, Université Paris-Saclay, Orsay, France.
- 3CPCV, ENS, PSL, CNRS, Sorbonne Université, Paris, France.
Abstract
Pin1 is a peptidyl-prolyl isomerase involved in key signalling pathways and upregulated in different cancers, including Multiple Myeloma (MM), where it is linked to poor prognosis/drug resistance. Despite its therapeutic relevance, Pin1 remains challenging to target with conventional inhibitors thereby motivating interest in Targeted Protein Degradation (TPD) strategies. All reported Pin1-PROTACs rely on covalent Pin1 ligands, leaving non-covalent degraders largely unexplored. Since PROTACs (PROteolysis TArgeting Chimeras) act catalytically/reversibly, non-covalent designs are attractive. Here, we describe the design/synthesis/evaluation of 12 non-covalent potential Pin1-PROTACs (P1-P12) based on reversible peptidomimetic ligand and in a prodrug form to allow cell permeability. Despite rational design, stability and measurable target engagement, P1-P12 displayed none or very limited degradation activity, with the most active molecule, P3, achieving only 39% of Pin1 depletion in MM cells. To confirm Pin1 degradability in MM, MM1.R cells were treated with the covalent PROTAC P1D-34, which induced robust dose-dependent degradation (DC₅₀ = 3.16 µM, DMAX = 90%). Overall, while demonstrating the feasibility of Pin1 depletion in MM, this work highlights the challenge of achieving effective Pin1 degradation with non-covalent micromolar ligands, underscores the current advantage of covalent engagement, and provides a foundation for the future development of non-covalent Pin1 degraders.
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BibTeX
@article{meneghelli2026exploring,
title = {{Exploring Non-Covalent Pin1-PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line.}},
author = {Lorenzo Meneghelli and Stephanie Davidson and Ji-Hyung Choi and Sami Mohammed Daddi Moussa and Simon Nadal and Delphine Ravault and Ludovic Carlier and Maud Larregola and Julien Pytkowicz and Chiara Zanato},
journal = {Chemistry \& biodiversity},
year = {2026},
month = oct,
doi = {10.1002/cbdv.71850},
url = {https://europepmc.org/article/MED/42904861},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Exploring Non-Covalent Pin1-PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line.
AU - Lorenzo Meneghelli
AU - Stephanie Davidson
AU - Ji-Hyung Choi
AU - Sami Mohammed Daddi Moussa
AU - Simon Nadal
AU - Delphine Ravault
AU - Ludovic Carlier
AU - Maud Larregola
AU - Julien Pytkowicz
AU - Chiara Zanato
PY - 2026
DA - 2026/10/01
JO - Chemistry & biodiversity
DO - 10.1002/cbdv.71850
UR - https://europepmc.org/article/MED/42904861
AB - Pin1 is a peptidyl-prolyl isomerase involved in key signalling pathways and upregulated in different cancers, including Multiple Myeloma (MM), where it is linked to poor prognosis/drug resistance. Despite its therapeutic relevance, Pin1 remains challenging to target with conventional inhibitors thereby motivating interest in Targeted Protein Degradation (TPD) strategies. All reported Pin1-PROTACs rely on covalent Pin1 ligands, leaving non-covalent degraders largely unexplored. Since PROTACs (PROteolysis TArgeting Chimeras) act catalytically/reversibly, non-covalent designs are attractive. Here, we describe the design/synthesis/evaluation of 12 non-covalent potential Pin1-PROTACs (P1-P12) based on reversible peptidomimetic ligand and in a prodrug form to allow cell permeability. Despite rational design, stability and measurable target engagement, P1-P12 displayed none or very limited degradation activity, with the most active molecule, P3, achieving only 39% of Pin1 depletion in MM cells. To confirm Pin1 degradability in MM, MM1.R cells were treated with the covalent PROTAC P1D-34, which induced robust dose-dependent degradation (DC₅₀ = 3.16 µM, DMAX = 90%). Overall, while demonstrating the feasibility of Pin1 depletion in MM, this work highlights the challenge of achieving effective Pin1 degradation with non-covalent micromolar ligands, underscores the current advantage of covalent engagement, and provides a foundation for the future development of non-covalent Pin1 degraders.
SN - 1612-1872
SN - 1612-1880
ER -