Discovery Of Novel Anti-tumor Compounds And Their Molecular Mechanism Study

Cancer is one of the major diseases causing death in the world,and it poses a serious threat to human health.Despite the evolving development of small-molecules based therapeutics,there are still a large parts of cancers lack effective treatment strategy.Moreover,the long-term use of existing small molecule drugs has led to the emergence of drug resistance.Therefore developing small molecule anti-cancer drugs with novel mechanisms or targeting new targets is the frontier and hotspot of drug development currently,and possesses economical and social significance.In this thesis,a series of compounds with the ability to induce cell vacuolization in triple negative breast cancer cells MDA-MB-231 were identified by phenotypic screening.Among them,HZX-02-059-01 could not only significantly induce cell vacuolization,but also showed potent anti-tumor activity and selectivity.Further molecular mechanism investigation revealed that HZX-02-059-01 inhibited PIKfyve,decreased the level of PI(3,5)P2,and disrupted endo-lysosomal system,which ultimately led to cell vacuolization.Additionally,HZX-02-059-01 inhibited tubulin polymerization and disrupted mitotic spindles,which led to cells arrest in M phase and induced apoptotic cell death.Further study revealed inhibition of tubulin polymerization by HZX-02-059-01,but not the induction of cell vacuolization,contributed to cancer cell death.Using HZX-02-059-01 as a lead,HW-06-151-01,which obtains better selectivity and activity,was further selected via structure/acitivity releationship optimization.In summary,we have discovered a new series of compounds with potent anti-cancer activity.Using HZX-02-59-01 as a tool,we have identified its cellular targests of PIKfyve and tublin,and dissected the molecular mechanism that led to cancer cell death.PIKfyve inhibitor HW-06-151-01 was obtained with improved selectivity and activity.HZX-02-59-01 and HW-06-151-01 will serve as good starting points for developing new therapies targeting both PIKfyve and tublin,and PIKfyve alone,respectively.