Design,Synthesis And Activity Of Small Molecular Inhibitors Targeting Porcupine Protein

The relatively conservative Wnt signaling pathway plays an important role in apoptosis,differentiation and other functions,and is closely related to a variety of functions of the body,such as bone,endocrine and so on.In adulthood,Wnt signaling pathway is generally inactivated,if abnormally activated,it may induce colon cancer,breast cancer and other cancers.Porcupine protein is a kind of membrane protein in this pathway,which is mainly distributed in the endoplasmic reticulum,acts on the secretion of Wnt protein,and has the functions of regulating cell migration and stem cell differentiation.Wnt protein secreted by ribosome can exert its biological activity only after its serine is palmitoylated by Porcupine protein.Therefore,Porcupine can be used as the target of drug molecules,inhibit its activity,and then block the abnormal activation of Wnt signal pathway to achieve the role of cancer treatment.LGK974 and ETC-159 are the only two small molecular inhibitors of Porcupine that have entered clinical trials.These inhibitors are very promising to appear on the market and really solve a variety of human cancers.In this experiment,LGK974,IWP-L6 and DC-9 were used as reference compounds,and the compound 1 with good activity was obtained by using the basic principles of drug molecular design such as skeleton transition.Although the activity of the compound 1(IC50=0.27 nM)is higher than that of LGK974(IC50=0.55 nM),in STF reporter gene analysis,its clogP(4.76)is higher and its planarity is stronger.Therefore,this subject is mainly on the basis of the compound 1,combined with our previous experience,further structural transformation,in order to obtain flexible compounds with good activity and good clogP the compound 1 was divided into three parts for structural transformation:part A and C introduced heteroatoms,changed the type of molecular hybridization,and part B changed the position of N atoms.Finally,the compound 16(IC50=0.27 nM,clogP=2.23)with ideal activity and clogP was obtained.In the later stage,we mainly improved molecular flexibility and carried out drug metabolism experiments.