Structure-activity relationships of hydrophobic small molecule irreversible inhibitors of tissue transglutaminase.

ABSTRACT: Tissue transglutaminase (TG2) is both an enzyme and a G-protein that is implicated in many diseases, such that small molecule inhibitors of TG2 have broad potential as drugs or research tools. Previous work has demonstrated how the structure of EB-2-16, a highly potent irreversible inhibitor of TG2, has been optimised with respect to its warhead, tether and bridge moieties. In this work, we studied the structure-activity relationships of the pendant hydrophobic group of the scaffold. This confirmed the superior affinity conferred by the parent adamantyl moiety, over other cycloalkyl, aryl, biaryl and bridged biaryl groups. Additionally, some substituted adamantyl derivatives were shown to exhibit superior inhibitory efficiency over the parent inhibitor, with k _inact/K<

SUBMITTER: Wallace DA 

PROVIDER: S-EPMC12631574 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature