PACMA 31

PACMA 31 is an irreversible inhibitor of protein disulfide isomerase (PDI; IC₅₀ = 10 µM), an endoplasmic reticulum chaperone protein that catalyzes disulfide bond breakage, formation, and rearrangement.¹ It inhibits PDI chaperone activity in a concentration- and time-dependent manner in an insulin aggregation assay and is cytotoxic to OVCAR-8 and OVCAR-3 ovarian cancer cells (IC₅₀s = 0.9 and 0.32 µM, respectively). PACMA 31 binds to GPX4 and induces ferroptosis in OVCAR-8 and HT-1080 fibrosarcoma cells.^2,3 It also reduces tumor growth in an OVCAR-8 mouse xenograft model.¹

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1. Xu, S., Butkevich, A.N., Yamada, R., et al. Discovery of an orally active small-molecule irreversible inhibitor of protein disulfide isomerase for ovarian cancer treatment. Proc. Natl. Acad. Sci. USA 109(40), 16348-16353 (2012).

2. Yan, B., Ai, Y., Sun, Q., et al. Membrane damage during ferroptosis is caused by oxidation of phospholipids catalyzed by the oxidoreductases POR and CYB5R1. Mol. Cell 81(2), 1-15 (2020).

3. Chen, Y.-C., Oses-Prieto, J.A., Pope, L.E., et al. Reactivity-based probe of the iron(II)-dependent interactome identifies new cellular modulators of ferroptosis. J. Am. Chem. Soc. 142(45), 19085-19093 (2020).