366780-95-2Relevant academic research and scientific papers
Structure-Activity Relationships of Potent, Targeted Covalent Inhibitors That Abolish Both the Transamidation and GTP Binding Activities of Human Tissue Transglutaminase
Akbar, Abdullah,McNeil, Nicole M. R.,Albert, Marie R.,Ta, Viviane,Adhikary, Gautam,Bourgeois, Karine,Eckert, Richard L.,Keillor, Jeffrey W.
, p. 7910 - 7927 (2017/10/06)
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 (kinact/KI > 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.
TG2 INHIBITOR COMPOUNDS AND USES THEREOF
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Paragraph 00356; 00357, (2017/11/16)
There are provided Tissue Transglutaminase (TG2) inhibitor compounds, and compositions and methods of use thereof for the prevention or treatment of a cancer. Compounds of Formula I, and pharmaceutically acceptable salts thereof, are provided: Formula (I).
SAR development of lysine-based irreversible inhibitors of transglutaminase 2 for huntington's disease
Wityak, John,Prime, Michael E.,Brookfield, Frederick A.,Courtney, Stephen M.,Erfan, Sayeh,Johnsen, Siw,Johnson, Peter D.,Li, Marie,Marston, Richard W.,Reed, Laura,Vaidya, Darshan,Schaertl, Sabine,Pedret-Dunn, Anna,Beconi, Maria,MacDonald, Douglas,Mu?oz-Sanjuan, Ignacio,Dominguez, Celia
supporting information, p. 1024 - 1028 (2013/02/22)
We report a series of irreversible transglutaminase 2 inhibitors starting from a known lysine dipeptide bearing an acrylamide warhead. We established new SARs resulting in compounds demonstrating improved potency and better physical and calculated properties. Transglutaminase selectivity profiling and in vitro ADME properties of selected compounds are also reported.
Synthesis of dipeptide-bound epoxides and α,β-unsaturated amides as potential irreversible transglutaminase inhibitors
De Macedo, Pierre,Marrano, Claudio,Keillor, Jeffrey W
, p. 355 - 360 (2007/10/03)
Herein we report the synthesis of 24 novel peptides as potential irreversible inactivators of transglutaminase (TGase). These peptides were designed to resemble Cbz-L-Gly, known to be a good TGase substrate, and to include either α,β-unsaturated amide groups or the corresponding epoxide groups. The side chain length of the amino acid residue bearing the inhibitor group was also varied in order to permit investigation of this effect. Copyright
