The Effects And Mechanism Of Small Molecule Compounds YG-1,H7 In Hematological Malignancies

Despite the application of intensive chemotherapy and targeted therapy with rituximab have improved treatment outcomes of Burkitt lymphoma(BL)in children,the prognosis is poor in elderly adults.Therefore,discovery of novel agents to overcome this disease is urgently required.Accumulating evidences show that constitutive NF-?B activation is a hallmark of BL and inactivation of NF-?B pathway is an attractive therapeutic option.In this study,using a cell-based screening,we found that YG-1,a novel boron compound,significantly inhibited TNF?-induced NF-?B activation and downregulated NF-?B target genes.YG-1 inhibited proliferation and induced apoptosis of BL cell lines.However,YG-1 has no obvious toxicity against normal blood mononuclear cells.Intriguingly,although YG-1 inhibited the transcription activity of NF-?B,YG-1did not affect TNFa-induced I?B? degradation,RelA/p65 nuclear translocation andbinding to DNA.However,YG-1 significantly suppressed phosphorylation of RelA/p65 on Ser536,paralleld with inhibition of IKK phosphorylation.In vivo,YG-1 significantly suppressed the tumor growth and inhibited the NF-?B activity with inhibition of phosphorylation of RelA/p65 on Ser536.In conclusion,our results suggest that YG-1 is a novel noncanonical NF-?B inhibitor with promising anti-lymphoma activity in vitro and in vivo.Further revealing the mechanism of action of YG-1 may not only provide novel insight into the regulation of RelA/p65 but also provides novel strategy for the treament of BL.Identifying novel targets to enhance leukemia-cell differentiation is an urgent requirment.We have recently proposed that inhibiting the antioxidant enzyme peroxiredoxin I(Prdx ?)may induce leukemia-cell differentiation.However,this concept remains to be confirmed.In this work,we identified H7 as a novel Prdx ? inhibitor through virtual screening,in vitro activity assay,and surface plasmon resonance assay.Cellular thermal shift assay showed that H7 directly bound to Prdx ? but not to Prdxs ?-? in cells.H7 treatment also increased reactive oxygen species(ROS)level and cell differentiation in leukemia cells,as reflected by the upregulation of the cell surface differentiation marker CD11b/CD14 and the morphological maturation of cells.The differentiation-induction effect of H7 was further observed in some non-acute promyelocytic leukemia(APL)and primary leukemia cells apart from APL NB4 cells.Moreover,the ROS scavenger N-acetyl cysteine significantly reversed the H7-induced cell differentiation.We demonstrated as well that H7-induced cell differentiation was associated with the activation of the ROS-Erk1/2-C/EBP? axis.Finally,we showed H7 treatment induced cell differentiation in an APL mouse model.All of these data confirmed that Prdx ? was novel target for inducing leukemia-cell differentiation and that H7 was a novel lead compound for optimizing Prdx ? inhibition.