Out-licensing

Novel Class of Selective Tissue Transglutaminase Inhibitors: Inhibiting Endocytosis, Apoptosis and Cell Growth

Introduction/Background

Transglutaminases (TGases) comprise a multifunctional family of enzymes involved in the cross-linking of certain proteins through the formation of gamma-glutamyl-ε-lysine side chain bridges. Tissue TGase is implicated in diverse biological processes such as endocytosis, apoptosis and cell growth regulation. Recent findings have shown that the unregulated activities of tissue TGase are associated with disease states such as acne, cataracts, immune system diseases, psoriasis, Alzheimer's disease, Huntington's disease, Celiac disease, chronic renal failure and cancer metastasis. In an attempt to treat these diseases, several inhibitors of tissue TGase have been developed. However, therapeutic use of these inhibitors is limited due to their poor selectivity for tissue TGase, slow inhibitory kinetics, and/or poor solubility.

Aims/Hypothesis

Our research is focused on the development of novel inhibitors of tissue Tgase.

Research

The technology, developed by Dr. Keillor and Dr. Lubell from the Université de Montréal, is a novel class of reversible competitive inhibitors of tissue TGase. These inhibitors are small chemical entities that can be sorted into three subclasses, with lead compounds in each class. Structure-activity relationship (SAR) studies were performed. Over 50 compounds were synthesized and tested in a competitive assay. All of these subclasses displayed reversible inhibition of tissue TGase and were competitive with TGase acyl-donor substrates. Lead compounds were identified showing IC50 values in the low micro molar range. In addition, at concentrations approaching the limits of their solubility, most of these compounds had no discernable effect on the activities of Factor XIIIa, a TGase isoform, or caspase 3, a cysteine protease with an active site catalytic triad similar to that of tissue TGase.

Conclusion

We have elucidated a novel class of selective tissue transglutaminase inhibitors.

Relevance/Opportunity

These inhibitors have potential therapeutic applications in several pathologies including Huntington's disease, Celiac disease and chronic renal failure. A provisional patent application has been filed. Please enquire quoting reference no. VAL-514-UM regarding licensing or codevelopment partnerships.

Preclinical