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

  • J Med Chem. 2017 Sep 28;60(18):7910-7927. doi: 10.1021/acs.jmedchem.7b01070.
Abdullah Akbar  1 ,  Nicole M R McNeil  1 ,  Marie R Albert  1 ,  Viviane Ta  1 ,  Gautam Adhikary  2 ,  Karine Bourgeois  1 ,  Richard L Eckert  2 ,  Jeffrey W Keillor  1
Affiliations
  • 1. Department of Chemistry and Biomolecular Sciences, University of Ottawa , 10 Marie-Curie, Ottawa, Ontario K1N 6N5, Canada.
  • 2. Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine , Baltimore, Maryland 21201, United States.
PMID: 28858494 DOI: 10.1021/acs.jmedchem.7b01070
Abstract

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.

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