Optimization And Biological Activity Studies Of Peptide Inhibitors As Anti-colorectal Cancer Agents

Now,tumor has become one of the major diseases that threaten the human health.Colorectal cancer is one of the leading causes of lethal among people in the world.Currently,drugs targeting colon cancer are rare,the design and development of targeted anti-colon cancer drugs has been the focus of research and research difficulties in recent decades.Nowdays,therapeutic agents in the treatment of metastatic colorectal cancer are fluorouracil that are toxic with severe adverse reactions,Therefore,new agents with less toxic and less adverse reactions are urgent in clinical.At the same time,our deep understanding of the pathogenesis of cancer and emergence of newer molecular targets for colon cancer has created a powerful impact.Related research shows that the initial identification of the adenomatous polyposis coli gene as a related gene of the colon cancer.Mutation of APC is the early event in colon cancer,and mutant truncated APC protein which constitutively activates downstream protein Asef is found to cause the aberrant migration behavior of colon cancer cells.Therefore,inhibitors blocking the interaction between APC and Asef can be a plausible approach for the development of new therapies for the treatment of colorectal cancer.In this project,previous research based on the laboratory,Combining structural biology,bioinformatics and drug chemistry,we designed a series of APC-Asef interaction inhibitors.On this basis,we combined structural biology,biophysics and structure-activity relationships,we optimized a series of APC-Asef peptide inhibitors,the active of the peptide inhibitors has been improved significantly compared with the previous reported.This can provide new ideas and methods for the subsequent design of APC-Asef inhibitors.Furthermore,we based on iASPP and p53 interaction mechanism,exploring the related conditions for the expression and purification of iASPP(625-828)protein.Combinating related research reports,these can lay a foundation for the subsequent design iASPP-p53 protein protein interaction inhibitors.In conclusion,we performed an extensively methods and techniques of medicinal chemistry,chemical biology to optimize a series of peptide inhibitors.On the original basis,we optimized the better active APC/Asef inhibitors MAI-400 with the intramolecular hydrogen bond.At the same time,we provided a certain basis for the subsequent design of iASPP-p53 inhibitors.