Structure Studies For PI3K? And APC,drug Design And Optimization Based On The Structure

Cancer is becoming the second disease threat to human health worldwide.Traditional anti-cancer agents,which directly interfere with mitosis,DNA synthesis and repair systems,are often connected with drawbacks such as low efficiency and high toxicity.A number of key signaling pathways,which play an important role in tumorigenesis and cancer development,have been identified.Thereafter,small-molecular inhibitors specifically targeting these key molecules become new class of anti-cancer agents,providing one of the main opportunities to overcome human cancers.PI3K? and APC are two promising target for cancer treatment.Based on structural biology and computational simulation,small molecule inhibitors are designed and optimized,providing a good foundation for cancer treatment.The phosphatidylinositol 3-kinase(PI3K)signaling pathway plays important roles in cell proliferation,growth,and survival.Hyperactivated PI3 K is frequently found in a wide variety of human cancers,validating it as a promising target for cancer therapy.We determined the crystal structure of the human PI3K?-PI103 complex to unravel molecular interactions.Based on the structure,substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site.Interestingly,the crystal structure of the PI3K?-9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification.Thus,these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3K? inhibitors.Adenomatous Polyposis Coli is a gene responsible for the onset of familial adenomatouspolyposis(FAP).Mutation of APC is also seen in themajority of sporadic colorectal tumors and is an earlyevent in tumorigenesis.Sixty percent of APC mutation leads to the generation of abnormal stop codon and truncation mutant lacking C terminal,which is the major cause of FAP and sporadic colorectal tumors.Since truncated mutant APC present incolorectal tumour cells activate Asef constitutively and contributeto their aberrant migratory properties,design of the drugs blocking their interaction will be an effective means for the treatment of the cancer.Based on the crystal structure of APC-ARM and Asef-ABR complex,we obtained the MAI-72 polypeptide with very good inhibitory activity by screen and optimization.Furthermore,we obtained and analyzed the crystal structure of APC-ARM and MAI-72 complex,providing the basis for understanding the mechanism of APC and guarantee for effective treatment of cancer and optimization of following drugs.