Design,Synthesis And Bioassays For Inhibitors Of PI3K And APC/Asef

Malignant tumors are becoming one of the major diseases affecting human health in recent years.Traditional anti-tumor drug research often focuses on the process of cell proliferation,including mitosis,DNA synthesis and repair,but its side effects are very serious due to its low specificity.With the increasing identification of key signaling pathways and signaling molecules associated with the development of different types of tumors,researchers are turning their direction to the development of small molecule inhibitors for key targets.In this paper,PI3 K and APC/Asef inhibitors were designed and synthesized with their antitumor activities were further explored.The phosphatidylinositol 3-kinase(PI3K)family is involved in a variety of cellular signaling pathways that regulate biological processes which are critical for the development of many tumors including cell growth,survival,proliferation,angiogenesis,migration and metastasis..And PI3 K mutation is usually present in many human tumors in the form of aberrant activation,so PI3 K is a drug therapeutic target with great potential.Based on the previously reported PI3 K small molecule inhibitor PI103,we simplified and modified into 11 small molecule compounds.Among these inhibitors,the inhibitory activity of 1b is similar to that of PI103,but the molecular weight is significantly decreased,and the pharmacokinetics is relatively better.The potential,in addition to its growth inhibition of PI3K-activated cell lines,was further confirmed.The Adenomatous Polyposis Coli(APC)is a gene associated with colon cancer.APC gene mutation results in the production of a truncated APC protein,while the truncated APC protein continuously activates the GEF activity of the Asef protein.It plays a crucial role in the abnormal migration of colon cancer cells and the formation of the colon cancer.In this paper,based on the analysis of APC/Asef crystal composite structure,we selected the ARM domain of APC protein as the target,and based on the peptide inhibitor MAI-150 which was previously discovered by us,52 peptides were designed and synthesised.And MPI-01,which is the best-class inhibitor of APC found so far,reaches the IC50 of 0.25?M.According to the existing structure,binding activity and docking model,the structure-activity relationship(SAR)of these two types of inhibitors was initially obtained,which laid the foundation for the subsequent development of new PI3 K and APC/Asef inhibitors.