Construction Of PROTAC Library Based On PANAC Reaction And Screening Of Cell Activity

Triple-negative breast cancer(TNBC)accounts for approximately 10-15% of all breast cancers,and patients with TNBC have a poorer prognosis compared to other subtypes of breast cancer.Due to its powerful aggressiveness and lack of effective targeted therapies,TNBC has become a dangerous malignancy.Immunotherapy continues to show excellent efficacy in a wide range of cancers,and given the current limited therapeutic options for TNBC,the development of targeted therapeutic approaches may be a promising strategy for TNBC.inhibitors of CDKs play an important role in controlling the cell cycle,which not only alleviates the symptoms of human cancers but also opens up new opportunities for cancer treatment,and thus it has great potential.PROTAC(targeted protein degradation)is a dual-function small molecule that consists of a target protein ligand,an E3 ubiquitin ligase ligand,and a series of linked chains that are efficiently linked together to achieve protein degradation.The mechanism of action of PROTACs and their great potential for biological research and disease treatment are of increasing interest to researchers,and more and more targets are proving to be degraded by PROTACs.According to the latest statistics in February2022,PROTACs can induce the degradation of more than 130 target proteins,including cancer,immune disorders,viral infections,neurodegenerative diseases,etc.More than10 PROTACs have already entered clinical studies.However,there are currently no universally accepted rules for the design of PROTACs and the selection of linker chains,which usually require a certain degree of experience and experimentation.Traditional development methods require stepwise synthesis,which is time-consuming and labor-intensive.Therefore,rapid construction of large libraries of PROTAC compounds for activity screening is the future direction of PROTAC technology.The use of click chemistry has been shown to be effective for the construction of PROTAC libraries,and the PANAC reaction,a novel photoclick chemistry reaction that enables the cross-linking of o-nitrobenzyl alcohol with primary amines to generate stable indazolone products,is equally efficient and highly selective,and has been widely used in biofluorescent labeling,DNA-protein cross-linking and codonexpanded protein targeted insertion The same efficient and selective characteristics have been widely used in biofluorescent labeling,DNA-protein cross-linking and codon expansion for protein targeted insertion studies.In this work,we synthesized several CDK ligands and E3 ligands with amine side chains using the PANAC reaction,introduced o-nitrobenzyl alcohol by one-step amide condensation,then added another ligand and reacted it with light,and constructed a library to obtain PROTAC assembly products rapidly.A total of 58 compounds with good data were obtained.The good cytostatic activity in triple-negative breast cancer cell lines was confirmed by activity reassays.To a certain extent,this experimental progress provides a platform for the rapid construction of drug molecules for the treatment of triple-negative breast cancer and lays the foundation for the development of future drugs for the treatment of triple-negative breast cancer disease.