Effect Of Cyclic Adenosine Phosphate-Activated Exchange Protein-1 Inhibitor (NY0123) On Breast Cancer

Breast cancer is a significant factors threatening women's health.In recent years,the incidence of breast tumor is the highest in women's cancer incidence,and the age of onset is younger.The growth of tumor is inseparable from the abnormal proliferation of tumor cells and the supply of oxygen and nutrients to new blood vessels.At present,the treatment methods for breast cancer patients are mainly targeted to inhibit tumor,anti-angiogenic drugs and chemotherapy drugs,the pathogenesis of tumor is very complicated,the current treatment methods still have many deficiencies,so look for more target-inhibitors will be benefit for the clinical treatment.Exchange proteins directly activated by cAMP(Epac1)is a guanine nucleotide exchange factors(GEFs)that is widely expressed in various tissues of mammals and promotes various diseases.Inhibition of Epac1 protein activity could inhibit the proliferation of vascular endothelial cells and inhibit angiogenesis;inhibition of Epac1 by small molecule inhibitors could inhibit the metastasis of breast cancer and induce tumor cell apoptosis.Therefore,Epac1 could be used as a therapeutic target for breast cancer,providing newideas for the treatment of breast cancer.At present,there are mainly ESI-09 and HJC0350 for Epac family protein inhibitors,but ESI-09 has a lower selective binding ability to Epac1 than Epac2,and HJC0350 is a selective Epac2 inhibitor.Therefore,if a small molecule compound can be designed and synthesized,the efficient selective inhibition of Epac1 function will provide a new therapeutic drug for breast cancer.This paper targets to design and synthesize Epac1 specific binding inhibitors and study their effects on breast cancer.According to the spatial conformation of Epac1 protein,a small molecule compound NY0123 which can selectively bind to Epac1 protein.Using chicken embryo chorioallantoic membrane(CAM)experimental tumor model and 4T1 cell mouse subcutaneous implant tumor model,they were determined that NY0123 had an inhibitory effect on tumor growth;and through angiogenesis models,such as chicken embryo CAM model,chicken embryo yolk sac film(YSM)model,mouse subcutaneous matrigel embolization model,rat arterial ring angiogenesis model,vascular endothelial cell tube formation and migration experiments,they were determined that NY0123 could inhibit angiogenesis.Moreover,NY0123 inhibited the formation and migration of vascular endothelial cells significantly higher than ESI-09.NY0123 also significantly inhibited cell proliferation and cell cycle progression in breast cancer,and promoted apoptosis,and its effects were significantly higher than ESI-09.In this study,we designed and synthesized Epac1 protein to selectively bind small molecule inhibitor NY0123,which was determined to inhibit the growth of tumor angiogenesis and tumor cell growth and promote its apoptosis by inhibiting Epac1,leading to inhibition of breast tumor growth.