Design,Synthesis And Activity Study Of LY-2940680 Derivatives Based On Hedgehog Signaling Pathway

Cancer has become one of the most serious diseases threatening human life and health.With the development of molecular biology and genetics and the progress of disease diagnosis and treatment,the understanding of the etiology of cancer is becoming more and more in-depth and cancer therapy has evolved from traditional radiotherapy and chemotherapy to molecular targeted therapy.Aberrant activation of the Hedgehog signaling pathway is associated with the formation of many cancers,such as basal cell carcinoma,medulloblastoma and breast cancer;the study also found that the Hedgehog signaling pathway is associated with cancer stem cells.At present,the inhibitors of different key components of Hedgehog signaling pathway include SHH inhibitors,SMO inhibitors and GLI inhibitors.GDC-0449(Vismodegib)is the first SMO inhibitor developed by Curis/Evotech/Genentech to be approved by the FDA in 2012 for the treatment of metastatic and locally advanced basal cell carcinoma;NVP-LDE225(Sonidegib),developed by Novartis,was approved by FDA in 2015 for the treatment of locally advanced basal cell carcinoma.Therefore,it is of great significance to design and develop a low toxic and highly effective antitumor drug to treat cancer by targeting Hedgehog signaling pathway.In this paper,the mechanism of Hedgehog signaling pathway and the research progress of its inhibitors were reviewed,and two series of 20 Hedgehog small molecule inhibitors with novel structure and targeting to SMO receptor were designed and synthesized using a small molecule inhibitor LY-2940680 in phase ? clinical study as a precursor;and a new and efficient process route of LY-2940680 was developed.In addition,by high throughput virtual screening of Zinc library,17 compounds with good inhibitory activity against SMO receptor were also found.In vitro cytotoxicity assay and Gli luciferase reporter assay showed that the target compounds LA-3,LC-1 and LE-5 not only had good inhibitory activity on breast cancer cell line MCF-7 but also exhibited good Hedgehog signal inhibitory activity,they can be used as a preferred Hedgehog small molecule inhibitors for further in vivo biological evaluation,and developed as anticancer drugs for the treatment of cancer related Hedgehog signaling pathway.