Abdullah Akbar, Nicole M.R. McNeil, Marie R. Albert, Viviane Ta, Gautam Adhikary, Karine Bourgeois, Richard L. Eckert, and Jeffrey W. Keillor
J. Med. Chem., 2017
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 has 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 (kinact/KI > 105 M-1min-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.
