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ACS Chem Biol. 2013 Nov 15;8(11):2577-85. doi: 10.1021/cb4002602. Epub 2013 Sep 26.

Small molecule probe suitable for in situ profiling and inhibition of protein disulfide isomerase.

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  • 1Department of Chemistry, National University of Singapore , 3 Science Drive 3, Singapore 117543.


Proper folding of cellular proteins is assisted by protein disulfide isomerases (PDIs) in the endoplasmic reticulum of mammalian cells. Of the at least 21 PDI family members known in humans, the 57-kDa PDI has been found to be a potential therapeutic target for a variety of human diseases including cancer and neurodegenerative diseases. Consequently, small molecule PDI-targeting inhibitors have been actively pursued in recent years, and thus far, compounds possessing moderate inhibitory activities (IC50 between 0.1 and 100 μM against recombinant PDI) have been discovered. In this article, by using in situ proteome profiling experiments in combination with in vitro PDI enzymatic inhibition assays, we have discovered a phenyl vinyl sulfonate-containing small molecule (P1; shown) as a relatively potent and specific inhibitor of endogenous human PDI in several mammalian cancer cells (e.g., GI50 ∼ 4 μM). It also possesses an IC50 value of 1.7 ± 0.4 μM in an in vitro insulin aggregation assay. Our results indicate P1 is indeed a novel, cell-permeable small molecule PDI inhibitor, and the electrophilic vinyl sulfonate scaffold might serve as a starting point for future development of next-generation PDI inhibitors and probes.

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