Discovery of an internal alkyne warhead scaffold for irreversible hTG2 inhibition.

ABSTRACT: 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 transam

SUBMITTER: Mader LK 

PROVIDER: S-EPMC12560834 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature