Characterization of Aminobenzylphenols as Protein Disulfide Isomerase Inhibitors in Glioblastoma Cell Lines

Disulfide
bond formation is a critical post-translational modification
of newly synthesized polypeptides in the oxidizing environment of
the endoplasmic reticulum and is mediated by protein disulfide isomerase
(PDIA1). In this study, we report a series of α-aminobenzylphenol
analogues as potent PDI inhibitors. The lead compound, AS15, is a covalent nanomolar inhibitor of PDI, and the combination of AS15 analogues with glutathione synthesis inhibitor buthionine
sulfoximine (BSO) leads to synergistic cell growth inhibition. Using
nascent RNA sequencing, we show that an AS15 analogue
triggers the unfolded protein response in glioblastoma cells. A BODIPY-labeled
analogue binds proteins including PDIA1, suggesting that the compounds
are cell-permeable and reach the intended target. Taken together,
these findings demonstrate an extensive biochemical characterization
of a novel series of highly potent reactive small molecules that covalently
bind to PDI.