New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds

Abstract

Transglutaminase 2 (EC 2.3.2.13; TG2 or TGase 2) plays important roles in the pathogenesis of many diseases, including cancers, neurodegeneration, and inflammatory disorders. Under normal conditions, however, mice lacking TGase 2 exhibit no obvious abnormal phenotype. TGase 2 expression is induced by chemical, physical, and viral stresses through tissue-protective signaling pathways. After stress dissipates, expression is normalized by feedback mechanisms. Dysregulation of TGase 2 expression under pathologic conditions, however, can potentiate pathogenesis and aggravate disease severity. Consistent with this, TGase 2 knockout mice exhibit reversal of disease phenotypes in neurodegenerative and chronic inflammatory disease models. Accordingly, TGase 2 is considered to be a potential therapeutic target. Based on structure–activity relationship assays performed over the past few decades, TGase 2 inhibitors have been developed that target the enzyme’s active site, but clinically applicable inhibitors are not yet available. The recently described the small molecule GK921, which lacks a group that can react with the active site of TGase 2, and efficiently inhibits the enzyme’s activity. Mechanistic studies revealed that GK921 binds at an allosteric binding site in the N-terminus of TGase 2 (amino acids (a.a.) 81–116), triggering a conformational change that inactivates the enzyme. Because the binding site of GK921 overlaps with the p53-binding site of TGase 2, the drug induces apoptosis in renal cell carcinoma by stabilizing p53. In this review, we discuss the possibility of developing TGase 2 inhibitors that target the allosteric binding site of TGase 2.

A Precision Strategy to Cure Renal Cell Carcinoma by Targeting Transglutaminase 2

“…Although these inhibitors were reported to induce a conformational change of TGase 2 that affects GTP binding to TGase 2, the binding of these inhibitors to TGase 2 did not apparently block p53 binding to TGase 2. This result corroborates previous reports regarding p53 binding to TGase 2, in that it is specifically the N-terminus of p53 that interacted with the N-terminus of TGase 2 [21][22][23]64]. This suggests indirectly that streptonigrin induced p53 activation by competing with p53 for binding to TGase 2 [23].…”

“…This is only possible in ccRCC because over 90% of p53 in ccRCC is wild type. Thus, collectively these observations represent a breakthrough for the clinical field because they identify TGase 2 as a specific therapeutic target for ccRCC, and the marked potential for binding inhibitors between TGase 2 and p53 such as GK921 [71] and streptonigrin [23] to become the first therapeutics for ccRCC (reviewed in [64]).…”

“…However, in ccRCC, TGase 2 is over 90% positive and plays a major role in suppressing wild type p53 [21]. The impact of this correlation is significant, as it indicates that TGase 2 can be a specific target for ccRCC therapy and that inhibitors such as GK921 and streptonigrin, which inhibit binding between TGase 2 and p53, can be an anti-cancer therapeutics [23,64].…”

“…(D) TGase 2 expression is also induced by anti-cancer drug treatment along with drug resistance through NF-B activation [42,70]. All of these pathways can be reversed by a single treatment of GK921 [71] or streptonigrin [23], which binds to the N-terminus of TGase 2 where p53 would bind, prior to transfer to the autophagosome in ccRCC [64].…”

Hypoxia-Dependent Expression of TG2 Isoforms in Neuroblastoma Cells as Consequence of Different MYCN Amplification Status

“…Several reports proposed TG2 inhibition as a useful tool for therapeutic approaches. For example, it has been reported that the GK921 TG2 inhibitor, overlapping with the p53-binding site of TG2, was able to induce apoptosis in renal cell carcinoma [37]. Similarly, the inhibition of TG2 by the microRNA (miR)-214 was associated with a relevant suppression of viability, invasion and migration of colorectal carcinoma cells [36].…”