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_m > 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.

葡萄糖调节蛋白78 kDa（GRP78）是一种有吸引力的抗血管生成和抗癌靶标，因为它选择性地堆积在癌细胞和癌细胞的内皮细胞而不是正常细胞的表面。在这项研究中，我们鉴定了一系列与GRP78结合的新型小分子，它们表现出有效的抗血管生成和抗癌活性，而不会影响正常细胞。其中，FL5,2-（4-（（4-乙酰氨基苯氧基）甲基）苯基）-N-异丁基苯并呋喃-3-羧酰胺由于与GRP78的强结合亲和力（T _m  > 2的增加）而优于其他化合物。°C可稳定GRP78蛋白），并具有针对人脐静脉内皮细胞（HUVEC）的有效抗血管生成和抗癌活性（EC ₅₀ = 1.514μM）和人肾癌细胞（786-O）（10μM时细胞死亡50％）。此外，FL5对小鼠成纤维细胞（Swiss-3T3）没有细胞毒性，后者在正常条件下不具有细胞表面GRP78。从虚拟对接研究中可以看出，FL5对ATPase活性的危害较小，后者对正常细胞至关重要。这项研究报告发现了靶向GRP78的新型小分子，具有强大的抗血管生成和抗癌活性，并且对正常细胞的毒性较小，这为癌症治疗的新途径提供了原型候选。