Discovery Of Potential Therapeutic Targets And Candidate Drugs Based On Multiple-omics Data

1.Background and aims:Complex disease is a kind of disease caused by multiple genes or environmental factors,with complex pathogenic mechanism and obvious heterogeneity.The common complex diseases include cancer,metabolism diseases,arthritis and asthma and so on.With the increasing incidence of complex diseases,the healthy of patients was severely affected.Combination therapeutics with multiple drugs are often used for clinical treatment,but the efficacy is unsatisfactory.Therefore,it is urgent to find new drug targets for complex diseases and provide new strategies for the treatment of patients,giving hope for the recovery of diseases.Drug development is an important part of the process for human struggling against disease.Traditional drug development is expensive and often takes more than10 years.In recent years,the rapid development of sequencing technology and bioinformatics analysis technology and the emergence of scientific databases have brought about great changes in drug research.They provide massive data support and powerful analysis ability to screen disease targets or drugs rapidly and efficiently,which shortening the period of drug development.In this study,we used bioinformation technology to analyze omics data.We screened drugs for two complex diseases with two different models,cancer and metabolic diseases,and clarified the therapeutic effect and molecular mechanism of drugs in vitro.2.Contents and results1)Screening of potential therapeutic target for NSCLC and identification of candidate drug:In this study,we screened drugs for cancer and metabolism diseases using omics analysis,further studies were performed to clarify the effects and molecular mechanism of the drugs on the disease-related cell models.In cancer research,our group focused on CDK family genes and carried out screening for therapeutic targets of non-small cell lung cancer(NSCLC)with genome-wide cell phenotype data(Depmap)and multiple data of tumor genome project.We found that CDK7 was the most indispensable gene for tumor cells survival from CDK family and was also significantly overexpressed in a variety of tumors,affecting the prognosis of patients significantly.In terms of molecular mechanism,we further confirmed that CDK7 inhibitor THZ1 can inhibit the cell proliferation and migration of multiple NSCLC cell lines.Meanwhile,THZ1 can also arrest cell cycle and induce cell apoptosis.Since the proliferation of tumor cells requires abundant metabolites and energy,we focused on the effects of THZ1 on the two most important metabolic pathways in tumor cells in the study of molecular mechanism.We found that THZ1 could interfere with the glycolysis pathway of NSCLC cells by inhibiting the Akt-mTOR signaling axis,and reduce the energy supply and the generation of metabolites in cancer cells.At the same time,we also found that THZ1 could reverse the expression of two glutaminase splicers by promoting the ubiquitination degradation of NUDT21,but had little effect on the overall glutaminase expression and metabolic pathway.Therefore,we used THZ1 combined with glutamine inhibitor cb-839 to treat NSCLC cell lines,and found that they showed a synergistic inhibitory effect on cell proliferation.These results suggest that CDK7-targeted inhibitor THZ1 may be a new lead compound for the treatment of NSCLC and providing a potential approach for drug development of NSCLC.2)Screening of potential therapeutic target for NAFLD and identification of candidate drug:For metabolic diseases,we focused on non-alcoholic fatty liver disease(NAFLD).our group constructed CMap of 73 compounds with HepG2 cell model.The screening identified histone deacetylase(HDAC)inhibitors as a potential drugs that could repress the lipid metabolism related pathways(fatty acid metabolism,fatty acid biosynthesis,fatty acid prolongation,sterol biosynthesis and glyceride metabolism,etc.)for the treatment of NAFLD.Then,we selected the HDAC inhibitor(SAHA)approved by FDA to verify our hypothesis.The showed that SAHA could reduce the formation and deposition of lipid droplets in fatty liver cell model significantly.Furthermore,we determined that DGAT2,a key rate-limiting enzymefor triglyceride biosynthesis,was a target gene directly regulated by HDAC2 and SAHA could reduce DGAT2 expression by inhibiting HDAC2,reducing triglyceride synthesis in liver cells and alleviating lipid accumulation.These findings suggest that SAHA has potential therapeutic effects in the treatment of NAFLD.3.ConclusionIn conclusion,our study screened for potential therapeutic targets and candidate drugs based on multiple-omics data for NSCLC and NAFLD and identifie the therapeutic targets and the related small molecule inhibitors on these two diseases.We further verified these potential drug targets and clarified the molecular mechanism for THZ1 and SAHA in treatment of these disease with experiments,providing a new direction and strategy for the drug development of NSCLC and NAFLD.