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Discovery of small molecules targeting GRP78 for antiangiogenic and anticancer therapy
Yixue Qiao1, Charlotte Dsouza2, Abigail Ann Matthews2
1Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Abstract:
Glucose Regulated Protein 78 kDa (GRP78) is an attractive antiangiogenic and anticancer target for its selective accumulation on the surface of cancer cells and cancer endothelial cells rather than normal cells. In this study, we identified a novel series of small molecules that binds to GRP78, exhibiting potent antiangiogenic and anticancer activities without affecting normal cells. Among these, FL5,2-(4-((4-acetamidophenoxy)methyl)phenyl)-N-isobutylbenzofuran-3-carboxamide, was superior to others due to its strong binding affinity to GRP78 (an increase in the Tm > 2 °C stabilising the GRP78 protein) and potent antiangiogenic and anticancer activities against human umbilical vein endothelial cells (HUVEC) (EC50 = 1.514 μM) and human renal cancer cells (786-O) (50% cell death at 10 μM). Furthermore, FL5 displayed no cytotoxic activity towards mouse fibroblast cells (Swiss-3T3), which do not harbour cell surface GRP78 under normal condition. FL5 was less detrimental to ATPase activity, which is essential for normal cells, as seen in the virtual docking studies. This study reports the discovery of novel small molecules targeting GRP78 with potent antiangiogenic and anticancer activities and less toxicity to normal cells, which provides prototype candidates for novel paths for cancer therapy.
Insights
Researchers discovered novel small molecules targeting Glucose Regulated Protein 78 kDa (GRP78) for cancer therapy. These compounds show potent antiangiogenic and anticancer effects, sparing normal cells, with FL5 as a promising candidate.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Glucose Regulated Protein 78 kDa (GRP78) is overexpressed on cancer cells, making it a selective therapeutic target.
- Targeting GRP78 offers a strategy for antiangiogenic and anticancer therapies with reduced normal cell toxicity.
Purpose of the Study:
- To identify and characterize novel small molecules that bind to GRP78.
- To evaluate the antiangiogenic and anticancer potential of these molecules.
- To assess the safety profile of candidate molecules on normal cells.
Main Methods:
- Screening of small molecules for GRP78 binding using thermal shift assays.
- In vitro evaluation of antiangiogenic activity using human umbilical vein endothelial cells (HUVEC).
- In vitro assessment of anticancer activity against human renal cancer cells (786-O) and cytotoxicity on mouse fibroblast cells (Swiss-3T3).
- Virtual docking studies to predict interactions with GRP78 and ATPase activity.
Main Results:
- A novel series of small molecules targeting GRP78 were identified.
- Compound FL5 demonstrated strong binding affinity to GRP78 (Tm increase > 2°C).
- FL5 exhibited potent antiangiogenic (EC50 = 1.514 μM for HUVEC) and anticancer activities (50% cell death at 10 μM for 786-O) without significant toxicity to normal cells (Swiss-3T3) or detrimental effects on ATPase activity.
Conclusions:
- Novel small molecules targeting GRP78 have been discovered.
- FL5 shows significant potential as an antiangiogenic and anticancer agent with a favorable safety profile.
- These findings provide promising candidates for developing new cancer therapies targeting GRP78.
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