Structure-activity Relationship Of 2,6-disubstituted-3h-imidazo[4,5-b]Pyridine Derivatives And The Antitumor Mechanism And Druggability Evaluation Of GG041104

It is difficult to overcome cancers,and the treatment of triple-negative breast cancer is the most challenging treatment among breast cancers.In this dissertation,we chose 2,6-disubstituted-3H-imidazo[4,5-b]pyridine derivatives as the research object.We established the structure-activity relationship and identified a candidate compound against triple-negative breast cancer by screening the antitumor activity of these compounds.We screened 2,6-disubstituted-3H-imidazo[4,5-b]pyridine derivatives with antitumor activity,and found that the IC50 value of GG041104 was 1.7 ± 0.7 nM for inhibitory growth in MDA-MB231 cells,which was significantly stronger than that of other tumor cell lines.Our studies on xenograft tumor inhibition reveled that GG041104 inhibits the growth of MDA-MB231 xenograft tumors in nude mice without causing death and organ damage.Furthermore,our studies showed that GG041104 induces cell-cycle arrest in MDA-MB231 cells.After treatment with GG041104 in MDA-MB231 cells,the cell cycle of was arrested in G2/M phase.Our studies also revealed that GG041104 induced cell apoptosis in a time-dependent and dose-dependent manner.Moreover,GG041104 inhibited the cell migration of MDA-MB231.However,we checked cell-cycle associated proteins like p53,CDK1,CDK9,cyclin B1 and cyclin T1,and the level of these proteins were not significantly change.It is suggested that the molecular mechanism of the anticancer activity of GG041104 needs to be further verified.Therefore,we used the approach of protein proteolysis-targeting chimeras(PROTACs)strategy to find drug targets of GG041104.We modified and designed functional PROTACs molecules based on GG041104,and obtained two functional molecules named GG041104-1-Po and GG041104-2-Po,the IC50 values were 470.7 ±68.2 and 275.7 ± 6.7 nM,respectively.Functional molecules arrest the cell cycle and induce cell apoptosis of MDA-MB231 cells.Moreover,our studies showed GG041104-1-Po and GG041104-2-Po down-regulate the expression of nuclear receptor RARy which was significantly lower than that of their original molecules.These results indicated that the PROTACs functional molecules showed the antitumor activity.It means that these two compounds are used for targeted degradation strategies for further study.In summary,this dissertation confirmed that 2,6-disubstituted-3H-imidazo[4,5-b]pyridine derivatives have a significant inhibitory effect on a variety of tumor cells.This study demonstrated that GG041104 might represent a novel candidate as a therapeutic agent for triple-negative breast cancer treatment.Therefore,an in-depth study of the antitumor targets and mechanisms of GG041104 is not only conducive to the development of new targeted agents for the treatment of triple-negative breast cancer but also provides new ideas for the design and synthesis of more effective antitumor agents.