2. Academic Validation
  3. Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2)

Discovery and Characterization of PROTACs Targeting Tissue Transglutaminase (TG2)

  • J Med Chem. 2023 Jul 14. doi: 10.1021/acs.jmedchem.2c01859.
Andres Valdivia 1,  Purav P Vagadia 2,  Guangxu Guo 3,  Eilidh O'Brien 1,  Daniela Matei 1 4 5,  Gary E Schiltz 2 4 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
  • 2 Department of Chemistry, Northwestern University, Evanston, Illinois 60208, United States.
  • 3 WuXi AppTec, Shanghai 200131, People's Republic of China.
  • 4 Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, United States.
  • 5 Jesse Brown VA Medical Center, Chicago, Illinois 60612, United States.
  • 6 Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, United States.
PMID: 37449845 DOI: 10.1021/acs.jmedchem.2c01859
Abstract

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.

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