YUM70 is a GRP78 inhibitor with IC50 value of 1.5μM and resulted in ER stress-mediated apoptosis. It inhibited pancreatic cancer cell growth in vitro and showed in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues.
Glucose-regulated protein 78 (GRP78) is a stress-inducible molecular chaperone expressed within the endoplasmic reticulum where it acts as a master regulator of the unfolded protein response (UPR) pathway. At times of ER stress, activation of the UPR, a multimolecular pathway, limits proteotoxicity induced by misfolded proteins. In malignancies, including multiple myeloma which is characterized by an accumulation of misfolded immunoglobulins, GRP78 expression is increased, with notable translocation of GRP78 to the cell surface[2].The ability of GRP78 to respond to endoplasmic reticulum stress (ERS) determines whether tumor cells survive and whether the changes in expression level of GRP78 regulated by endoplasmic reticulum (ER) caused by various factors will directly or indirectly affect cell proliferation, apoptosis, and injury, or reduce the body's defense ability, or have protective effects on various organs[3]. Cell-surface GRP78 has emerged as an important regulator of tumour cell signalling and viability as it forms complexes with a rapidly expanding repertoire of cell-surface protein partners, regulating proliferation, PI3K (phosphoinositide 3-kinase)/Akt signalling and cell viability[4].YUM70 is a potent and selective glucose-regulated protein 78 (GRP78) inhibitor(with an IC50 of 1.5 μM for inhibiting GRP78 ATPase activity of the full-length protein). It induces endoplasmic reticulum (ER) stress-mediated apoptosis in pancreatic cancer. YUM70, inhibited pancreatic cancer cell growth in vitro.YUM70 directly bound GRP78 and inactivated its function, resulting in ER stress-mediated apoptosis. A YUM70 analog conjugated with BODIPY show co-localization of the compound with GRP78 in the ER. YUM70 in vivo efficacy in a pancreatic cancer xenograft model with no toxicity to normal tissues.YUM70 is a novel inducer of ER stress with preclinical efficacy as a monotherapy or in combination with topoisomerase and HDAC inhibitors in pancreatic cancer.[5].
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