Tissue transglutaminase (TG2) is a multifunctional enzyme involved in the cross-linking of extracellular matrix proteins, formation of complexes with fibronectin (FN) and integrins, and GTP hydrolysis. TG2 is activated in several pathological conditions, including cancer. We recently described a novel series of ligands that bind to TG2 and inhibit its interaction with FN. Because TG2 acts via multiple mechanisms, we set out to pursue a targeted protein degradation strategy to abolish TG2's myriad functions. Here, we report the synthesis and characterization of a series of VHL-based degraders that reduce TG2 in ovarian cancer cells in a proteasome-dependent manner. Degradation of TG2 resulted in significantly reduced cancer cell adhesion and migration in scratch-wound and migration assays. These results strongly indicate that further development of more potent and efficient TG2 degraders could be a new strategy for reducing the dissemination of ovarian and other cancers.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10388319PMC
http://dx.doi.org/10.1021/acs.jmedchem.2c01859DOI Listing

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