The Role And Mechanism Of USP2 And USP24 In Hematological Tumors

It is an effective strategy to find the important target by using active small molecule compound and explain the rule of cell life activity in modern medical research.Our study found that gambogic acid(GA)can effectively inhibit the survival and proliferation of multiple myeloma(MM)cells in vitro and in vivo.At the same time,we synthesized biotin-labeled GA(Biotin-GA)as a probe and used a series of chemical proteomics techniques to carry out its chemical biology research on MM.The results showed that GA can directly target deubiquitinated protease 2a(USP2a)and effectively inhibit the USP2 a enzyme activity.Next,it was confirmed by mass spectrometry and site mutation experiments that Cys284 of USP2 a is a covalent binding site of GA.In addition,the study found that USP2 a is highly expressed in MM and significantly negatively correlated with survival.Knocking down of USP2 a in MM cells significantly inhibited proliferation in vitro and in vivo.In summary,our study shows that GA mainly inhibits MM by inhibiting the USP2 a enzyme activity in vitro and in vivo.The Cys284 binding pocket of GA and USP2 a is expected to provide a reference for the development of specific and potent inhibitors of USP2 a.T-cell acute lymphoblastic leukemia(T-ALL)is a lymphoid malignant tumor caused by the oncogenic transformation of immature T cell progenitor cells with poor prognosis.It is urgent to identify new targets and develop new drugs to treat this disease.WP1130 is a deubiquitinase inhibitor(which inhibits USP9 X,USP24,etc.).Here,we found that WP1130 can effectively inhibit the proliferation of T-ALL cells and induce apoptosis.In addition,the results suggest that knockdown of USP24,but not USP9 X,significantly inhibits T-ALL cell growth and induces apoptosis.USP24 is up-regulated in T-ALL and is significantly negatively correlated with its survival.Through molecular docking and cellular thermal shift assay,we further demonstrated that WP1130 directly interacts with the active site pocket of USP24 in T-ALL cells,thereby inhibiting its activity leading to a decrease in its substrate Mcl-1.Consistent with this,when USP24 was reactivated,WP1130-induced apoptosis of T-ALL cells was partially blocked.In addition,we also found that WP1130 induced apoptosis is associated with disruption of mitochondrial transmembrane potential.Finally,through the xenograft model we found that WP1130 also significantly inhibited T-ALL in vivo.Taken together,we believe that targeting the USP24-Mcl-1 axis may represent a new therapeutic T-ALL strategy,and WP1130 is a lead compound for the development of anti-T-ALL drugs.