Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2)

作者：Andres Valdivia, Purav P. Vagadia, Guangxu Guo, Eilidh O’Brien, Daniela Matei, Gary E. Schiltz · 发表于：Journal of Medicinal Chemistry · 年份：2023 · DOI：10.1021/acs.jmedchem.2c01859 · 被引用次数：9 · 研究领域：Protein Degradation and Inhibitors、Ubiquitin and proteasome pathways、CAR-T cell therapy research

High Resolution Image Download MS PowerPoint Slide 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.