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Article Abstract
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 DC values. Among these, the lead compound DBVR-PTC-02 exhibited exceptional potency, with DC values of 42 nM (D = 90 %) for GSK-3β and 48 nM (D = 88 %) for CDK5. DBVR-PTC-02 also displayed superior antiproliferative activity compared to single-target PROTACs and conventional kinase inhibitors, with an IC 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.
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| http://dx.doi.org/10.1016/j.bmc.2025.118085 | DOI Listing |
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