Novel dual-targeting PROTAC degraders of GSK-3β and CDK5: A promising approach for pancreatic cancer treatment.

Pancreatic cancer remains one of the most lethal malignancies, characterized by limited therapeutic options and poor prognoses. Here, we report the development of novel dual-targeting PROTAC (proteolysis-targeting chimera) compounds designed to concurrently degrade GSK-3β and CDK5. These bifunctional molecules were systematically designed by integrating three critical components: (1) a ligand that selectively binds GSK-3β and CDK5, (2) an E3 ligase-recruiting motif, and (3) an optimized linker to facilitate target engagement and proteasomal degradation. Our series of compounds (DBMG-01 through DBVR-PTC-02) demonstrated robust and selective target degradation in pancreatic cancer cell lines, achieving nanomolar DC50 values. Among these, the lead compound DBVR-PTC-02 exhibited exceptional potency, with DC50 values of 42 nM (Dmax = 90 %) for GSK-3β and 48 nM (Dmax = 88 %) for CDK5. DBVR-PTC-02 also displayed superior antiproliferative activity compared to single-target PROTACs and conventional kinase inhibitors, with an IC50 of 1.81 ± 0.55 µM in pancreatic cancer cell viability assays. This study establishes a novel framework for dual-targeted protein degradation and highlights the therapeutic potential of DBVR-PTC-02 as a promising candidate for the treatment of pancreatic cancer.