Design, Synthesis, and Biological Evaluation of Novel Allosteric Protein Disulfide Isomerase Inhibitors

Protein
disulfide isomerase (PDI) is responsible for nascent protein folding
in the endoplasmic reticulum (ER) and is critical for glioblastoma
survival. To improve the potency of lead PDI inhibitor BAP2 ((E)-3-(3-(4-hydroxyphenyl)-3-oxoprop-1-en-1-yl)­benzonitrile),
we designed and synthesized 67 analogues. We determined that
PDI inhibition relied on the A ring hydroxyl group of the chalcone
scaffold and cLogP increase in the sulfonamide chain improved potency.
Docking studies revealed that BAP2 and analogues bind
to His256 in the b′ domain of PDI, and mutation of His256 to
Ala abolishes BAP2 analogue activity. BAP2 and optimized analogue 59 have modest thiol reactivity;
however, we propose that PDI inhibition by BAP2 analogues
depends on the b′ domain. Importantly, analogues inhibit glioblastoma
cell growth, induce ER stress, increase expression of G2M checkpoint
proteins, and reduce expression of DNA repair proteins. Cumulatively,
our results support inhibition of PDI as a novel strategy to treat
glioblastoma.