Structure–Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase

• Published in: Journal of medicinal chemistry Vol. 60; no. 18; pp. 7910 - 7927
• Main Authors: Akbar, Abdullah, McNeil, Nicole M. R, Albert, Marie R, Ta, Viviane, Adhikary, Gautam, Bourgeois, Karine, Eckert, Richard L, Keillor, Jeffrey W
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.09.2017; Amer Chemical Soc
• Subjects: Cell Line; Chemistry, Medicinal; Drug Design; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; GTP-Binding Proteins - antagonists & inhibitors; GTP-Binding Proteins - metabolism; Guanosine Triphosphate - metabolism; Humans; Life Sciences & Biomedicine; Neoplastic Stem Cells - cytology; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Pharmacology & Pharmacy; Protein Binding - drug effects; Science & Technology; Structure-Activity Relationship; Transglutaminases - antagonists & inhibitors; Transglutaminases - metabolism; KINETIC CAPILLARY-ELECTROPHORESIS; IRREVERSIBLE INHIBITORS; PROTEIN; PIG LIVER TRANSGLUTAMINASE; STEM-CELL SURVIVAL; ALPHA,BETA-UNSATURATED AMIDES; NUCLEOTIDE-BINDING; HUNTINGTONS-DISEASE; DERIVATIVES; CELIAC-DISEASE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01070

Human tissue transglutaminase (hTG2) is a multifunctional enzyme. It is primarily known for its calcium-dependent transamidation activity that leads to formation of an isopeptide bond between glutamine and lysine residues found on the surface of proteins, but it is also a GTP binding protein. Overexpression and unregulated hTG2 activity have been associated with numerous human diseases, including cancer stem cell survival and metastatic phenotype. Herein, we present a series of targeted covalent inhibitors (TCIs) based on our previously reported Cbz-Lys scaffold. From this structure–activity relationship (SAR) study, novel irreversible inhibitors were identified that block the transamidation activity of hTG2 and allosterically abolish its GTP binding ability with a high degree of selectivity and efficiency (k inact/K I > 105 M–1 min–1). One optimized inhibitor (VA4) was also shown to inhibit epidermal cancer stem cell invasion with an EC50 of 3.9 μM, representing a significant improvement over our previously reported “hit” NC9.