New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds
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 b...
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| Format: | Article |
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MDPI AG
2018-10-01
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| Series: | Medical Sciences |
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| Online Access: | http://www.mdpi.com/2076-3271/6/4/87 |
| _version_ | 1829143545710116864 |
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| author | Soo-Youl Kim |
| author_facet | Soo-Youl Kim |
| author_sort | Soo-Youl Kim |
| collection | DOAJ |
| description | 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. |
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| issn | 2076-3271 |
| language | English |
| last_indexed | 2024-12-14T20:52:29Z |
| publishDate | 2018-10-01 |
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| spelling | doaj.art-f8a3ad1b25084193bf0e7b4ef9739c502022-12-21T22:47:47ZengMDPI AGMedical Sciences2076-32712018-10-01648710.3390/medsci6040087medsci6040087New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead CompoundsSoo-Youl Kim0Tumor Microenvironment Research Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang 10408, KoreaTransglutaminase 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.http://www.mdpi.com/2076-3271/6/4/87transglutaminase 2inhibitorconformationdimerpolymerizationcross-linking |
| spellingShingle | Soo-Youl Kim New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds Medical Sciences transglutaminase 2 inhibitor conformation dimer polymerization cross-linking |
| title | New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds |
| title_full | New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds |
| title_fullStr | New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds |
| title_full_unstemmed | New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds |
| title_short | New Insights into Development of Transglutaminase 2 Inhibitors as Pharmaceutical Lead Compounds |
| title_sort | new insights into development of transglutaminase 2 inhibitors as pharmaceutical lead compounds |
| topic | transglutaminase 2 inhibitor conformation dimer polymerization cross-linking |
| url | http://www.mdpi.com/2076-3271/6/4/87 |
| work_keys_str_mv | AT sooyoulkim newinsightsintodevelopmentoftransglutaminase2inhibitorsaspharmaceuticalleadcompounds |