Exploring Non‐Covalent Pin1‐PROTACs Insights Into Degradation Efficiency in Multiple Myeloma Cell Line

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 (DC ₅₀  = 3.16 µM, D _MAX = 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.