The protein chaperone GRP78 is a master regulator of endoplasmic reticulum (ER) functions and is frequently over-expressed at the surface of cancer cells where it contributes to chemo-resistance. It represents a well-studied ER stress marker but an under-explored target for new drug development. This review aims to untangle the structural and functional diversity of GRP78 modulators, covering over 130 natural products, synthetic molecules, specific peptides and monoclonal antibodies that target GRP78. Several approaches to promote or to incapacitate GRP78 are presented, including the use of oligonucleotides and specific cell-delivery peptides often conjugated to cytotoxic payloads to design GRP78-targeted therapeutics. A repertoire of drugs that turn on/off GRP78 is exposed, including molecules which bind directly to GRP78, principally to its ATP site. There exist many options to regulate positively or negatively the expression of the chaperone, or to interfere with its cellular trafficking. This review provides a molecular cartography of GRP78 pharmacological effectors and adds weight to the notion that GRP78 repressors could represent promising anticancer therapeutics, notably as regards limiting chemo-resistance of cancer cells. The potential of GRP78-targeting drugs in other therapeutic modalities is also evoked.
Keywords: Anticancer drugs; Cancer; Chaperone; GRP78; Monoclonal antibodies; Natural products.
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