Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2)

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 vitro in scratch-wound and migration assays. These results
strongly indicate that further development of more potent and in vivo efficient TG2 degraders could be a new strategy
for reducing the dissemination of ovarian and other cancers.