The Study Of NUDT5 As A Therapeutic Drug Target And Prognostic Biomarker For ER-positive Breast Cancer

Breast cancer is the most common malignant tumor in women.It is a global disease with an increasing incidence year by year.Estrogen receptor positive（ER+）subtypes account for about 70%of all breast cancer patients.According to clinical data,although the prognosis of patients with ER+breast cancer is relatively good,the 5-year survival rate is only about 22.8%.It is still urgent to find new tumor markers and therapeutic drugs.Estrogen is the most important hormone affecting the occurrence and development of breast cancer.ATP,as an estrogen cofactor,can regulate the role of estrogen by mediating the process of phase separation in the nucleus.Related studies have shown that NUDT5（Nudix-Type Motif 5）is a key factor in the production of ATP in breast cancer cells nucleus.NUDT5 inhibitors can block nuclear ATP synthesis of breast cancer cells,restrain hormone signal transduction and inhibit cancer cell proliferation.It means that NUDT5 may become a novel drug target and biomarker for ER+breast cancer.However,it still takes a long time and a large number of experiments for the existing small molecular inhibitors to be put into clinical application.In this study,the strategy of"drug retargeting"was adopted.We tried to find potential drugs for ER+breast cancer in FDA-approved drugs.First of all,the information of drug target,gene,disease and expression profile data were collected from Connectivity Map（c Map）database.The drug similarity among 1,309 small molecular compounds was calculated.Small drug molecules similar to known estrogen antagonists were screened according to Tanimoto coefficient.Based on Drug Bank database,18 FDA-approved drugs were selected as potential NUDT5 inhibitors for follow-up research.Secondly,the molecular docking and molecular dynamics analysis were carried out to determine the binding mode of the candidate drugs.The results showed that all the 14 candidate drugs had 3 or more key active sites,which had the potential to target NUDT5.Then,according to the mechanism of drug molecular action and related experimental studies,7 candidate drugs were selected,and the half maximal inhibitory concentration(IC₅₀)was measured.The experimental results showed that all the 7 candidate drugs could inhibit the growth of MCF7 breast cancer cells.Finally,the gene expression data,survival time,survival status and other clinical information of patients with various subtypes of breast cancer were collected from The Cancer Genome Atlas（TCGA）database,and the survival time of the collected data was analyzed.The results showed that NUDT5 can well predict the prognosis of patients with ER+breast cancer and is expected to be a novel prognostic biomarker of ER+breast cancer.To sum up,this study preliminarily evaluated the potential of NUDT5 as a drug target and prognostic biomarker for the treatment of ER+breast cancer,and found the corresponding targeted therapeutic drugs.The effectiveness of the candidate drugs was proved by chemical structure and cell level experiments.This topic not only has a important application value for the clinical treatment of ER+breast cancer,but also provides new ideas for the related research fields of new drug discovery.