Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, 200240, China.
Department of Biological Sciences, Faculty of Science, National University of Singapore, 16 Science Drive 4, 117558, Singapore.
Eur J Med Chem. 2020 May 1;193:112228. doi: 10.1016/j.ejmech.2020.112228. Epub 2020 Mar 13.
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 T > 2 °C stabilising the GRP78 protein) and potent antiangiogenic and anticancer activities against human umbilical vein endothelial cells (HUVEC) (EC = 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.
葡萄糖调节蛋白 78kDa（GRP78）因其选择性地在癌细胞和癌细胞内皮细胞表面积累，而不是在正常细胞表面积累，因此成为一种有吸引力的抗血管生成和抗癌靶点。在这项研究中，我们鉴定了一系列新的小分子，这些小分子与 GRP78 结合，具有强大的抗血管生成和抗癌活性，而不影响正常细胞。在这些小分子中，FL5，2-（4-（（4-乙酰氨基苯氧基）甲基）苯基）-N-异丁基苯并呋喃-3-甲酰胺，因其与 GRP78 的强结合亲和力（增加 T > 2°C 稳定 GRP78 蛋白）和对人脐静脉内皮细胞（HUVEC）（EC = 1.514 μM）和人肾癌细胞（786-O）（在 10 μM 时 50%细胞死亡）的强大抗血管生成和抗癌活性而优于其他小分子。此外，FL5 对不表达细胞表面 GRP78 的正常条件下的小鼠成纤维细胞（Swiss-3T3）没有细胞毒性。在虚拟对接研究中，FL5 对正常细胞至关重要的 ATP 酶活性的损害较小。这项研究报告了发现靶向 GRP78 的新型小分子，具有强大的抗血管生成和抗癌活性，对正常细胞的毒性较小，为癌症治疗的新途径提供了原型候选物。
