Design, Synthesis And Activity Evaluation Of FAK Inhibitors

With the rapid development of molecular biology,many of the specific tumor cellsignal transduction pathway has been known.According to some important targets in thesespecific signal transduction pathways has become an important method for drug design，bythis method we can get high selectivity and low toxicity drug. The rapid growth and easydiffusion of tumor cells are the main reason of difficult to cure tumor. FAK is one ofnon-receptor tyrosine kinase, regulates a variety of cell functions. Excessive expression ofFAK has been detected in a large number of human cancer cells such as breast, prostatecancer, colon cancer, thyroid cancer, ovarian cancer, etc. The action of integrin and growthfactor receptor, cause the auto-phosphorylation in Y397site of FAK, provides anappropriate binding site for proteins which contain SH2area or phosphotyrosine bindingsites, then activate a lot of downstream signal to regulate the proliferation, survival,migration and other aspect activities of tumor cells, so looking for highly active FAKinhibitors can selectively block the proliferation, survival, migration of tumor cells. It hasimportant significance on the treatment of cancer. On the present, there just have severaldrugs into clinical stage. The aim of this paper is to get some highly active and highselective compounds on the basis of previous work with the help of computer aided drugdesign software. Do something in pharmacology to primary evaluate its activity, for thenew anticancer drug design and structure optimization provide experimental and theoreticalsupport.The main contents and results of this object are as follows:1. The construction of pharmacophore model and the design of the targetcompoundsThrough consulting a large number of literatures，get active compounds structure andits IC50value, then use the Catalyst software to build a pharmacophore model, then use the new pharmacophore model to design new compounds.2. The synthesis and structural identificationThrough the exploration, design a rational synthesis route. At last, got5newcompounds. All structures were corroborated by spectra of UV, NMR, HPLC, MS.3. The initial evaluation of pharmacological activity and the validation ofpharmacophore modelSelecting two cell lines in which FAK express highly: MCF-7, Caco-2. Use MTTmethod to detect the inhibition rate to cancer cells. The experimental results show that thetarget compounds A-D have good inhibition to two kinds of cells. The action of E is notregularity, show some of protection. This compound pulses a thiazole group so it presentthe protection action. The D is action better than other compounds, especially to Caco-2cells. The IC50are equal to15.47μmol/L, it has potential of further development. Wecomparised the pharmacological activities of experimental value and pharmacophore modelprediction, we find that the prediction and experimental activity has a certain consistency.This result indicates that the pharmacophore model can guide the design of FAK inhibitors.4. Innovation pointsGet a new pharmacophore model of FAK inhibitors, synthesis5whole newcompounds, have improved the post-processing method of C-N coupling reaction whichwere catalyzed by cuprous iodide according to their characteristics of the compounds.