Lavleen K. Mader, Namita Maunick, Jessica E. Borean, Jeffrey W. Keillor
RSC Med. Chem., 2025
https://doi.org/10.1039/D5MD00777A
Human tissue transglutaminase (hTG2) is a multifunctional enzyme with both protein
cross-linking and G-protein activity. Dysregulation of these functions has been implicated in
diseases such as celiac disease and cancer, prompting the development of hTG2 inhibitors, many
of which act covalently via a pendant electrophilic warhead. Most small molecule hTG2 inhibitors
to date feature terminal, sterically minimal warheads, based on the assumption that bulkier
electrophiles impair binding and reactivity. Here, we report structure–activity relationships (SAR)
of a novel internal alkynyl warhead scaffold for irreversible inhibition of hTG2. This series
includes one of the most potent non-peptidic hTG2 inhibitors reported to date. We demonstrate
that this scaffold not only inhibits transamidase activity but also abolishes GTP binding, while
exhibiting excellent isozyme selectivity. In addition, we investigate the tunability and stability of
this warhead, providing insights into its broader applicability. Through detailed kinetic analysis,
this study establishes a new scaffold for irreversible hTG2 inhibition and expands the design
principles for covalent warheads beyond traditional terminal systems.
