Protein disulfide isomerase family (PDI family)

The Protein Disulfide Isomerase (PDI) family, primarily represented by PDIA1 (PDI) and PDIA3 (ERp57), consists of essential endoplasmic reticulum (ER)-resident enzymes and molecular chaperones that catalyze the formation, isomerization, and reduction of disulfide bonds in nascent proteins [1.3.2, 1.5.4]. This activity is crucial for the proper folding and structural maturation of approximately one-third of the human proteome, including most secretory and membrane-bound proteins [1.3.2]. Beyond the ER, PDIs are also localized to the cell surface and extracellular space, where they regulate processes such as platelet activation, fibrin formation, and the entry of various viruses and toxins into host cells [1.1.1, 1.2.1, 1.3.4]. In pathological states, particularly cancer, PDI expression is frequently upregulated to support the high protein synthesis demands of malignant cells and to provide resistance against ER stress-induced apoptosis [1.1.2, 1.3.1]. Targeting the PDI family has emerged as a promising therapeutic strategy across multiple indications, including oncology, cardiovascular disease, and neurodegeneration [1.1.1, 1.2.2]. In cancer, PDI inhibitors like PACMA-31 and CCF642 induce proteotoxic stress and trigger the unfolded protein response (UPR), leading to apoptotic cell death, and have shown potential in treating glioblastoma, multiple myeloma, and prostate cancer [1.1.2, 1.1.3, 1.3.1]. In the context of thrombosis, the PDI inhibitor isoquercetin has reached Phase 2 clinical trials for reducing hypercoagulability in cancer patients by blocking extracellular PDI activity [1.2.2]. Despite their therapeutic potential, a significant challenge remains in developing isoform-selective inhibitors to minimize systemic toxicity, as PDIs play fundamental roles in normal cellular protein homeostasis [1.1.1, 1.3.4].

Other names

PDIA1PDIA3PDIERp57GRP58P4HBERp60ERp61GRP57P58PI-PLCProtein disulfide-isomerase A1Protein disulfide-isomerase A3PDIa

Inhibition of thiol-disulfide oxidoreductase activity, leading to disrupted protein folding, induction of the unfolded protein response (UPR), and apoptosis in cancer cells, or prevention of extracellular disulfide exchange in thrombosis.