Recent advances in small molecule and peptide inhibitors of glucose-regulated protein 78 for cancer therapy.

Glucose-regulated protein 78 (GRP78) is one of key endoplasmic reticulum (ER) chaperone proteins that regulates the unfolded protein response (UPR) to maintain ER homeostasis. As a core factor in the regulation of the UPR, GRP78 takes a critical part in the cellular processes required for tumorigenesis, such as proliferation, metastasis, anti-apoptosis, immune escape and chemoresistance. Overexpression of GRP78 is closely correlated with tumorigenesis and poor prognosis in various malignant tumors. Targeting GRP78 is regarded as a potentially promising therapeutic strategy for cancer therapy. Although none of the GRP78 inhibitors have been approved to date, there have been several studies of GRP78 inhibitors. Herein, we comprehensively review the structure, physiological functions of GRP78 and the recent progress of GRP78 inhibitors, and discuss the structures, in vitro and in vivo efficacies, and merits and demerits of these inhibitors to inspire further research. Additionally, the feasibility of GRP78-targeting proteolysis-targeting chimeras (PROTACs), disrupting GRP78 cochaperone interactions, or covalent inhibition are also discussed as novel strategies for drugs discovery targeting GRP78, with the hope that these strategies can provide new opportunities for targeted GRP78 antitumor therapy.