Functional And Mechanistic Studies On The Inhibition Of Acute Myeloid Leukemia By Topotecan Hydrochloride

Acute myeloid leukemia(AML)is the common form of acute leukemia in adults.The median age of AML patients is 68 years,and the incidence of AML increases with age.Thus,the number of AML patients is gradually increasing worldwide as the population aging situation develops.The American Cancer Society estimates that AML will cause 11,540 deaths in the United States in 2022,accounting for the highest percentage of leukemia deaths(48%).Despite recent rapid advances in targeted treatments and allogeneic stem cell transplantation,the 5-year survival rate in AML cases is still <50%,and leukemia recurrence is the one of the main reasons of treatment failure.Constitutive signal transducer and activator of transcription 5(STAT5)activation,usually a hallmark of hematologic malignancies,occurs in approximately 70% of patients with AML.FLT3-ITD mutations are associated with poor prognosis,short progression-free survival,and high recurrence rates in AML patients.STAT5 is activated by FLT3-ITD and drives the pathogenesis of AML.High STAT5 expression is associated with drug resistance,and direct targeting of STAT5 has important clinical value for AML.There are several inhibitors that interact with STAT5 to inhibit its activity,but none of them are very effective therapeutically.Therefore,it is urgent to develop a STAT5 small molecule inhibitor to improve the prognosis of AML patients.In this study,we designed and established a high throughput fluorescence polarization(FP)screening system for STAT5,screened the existing compound library in the laboratory,and obtained a highly active small molecule inhibitor topotecan hydrochloride(108).Topotecan hydrochloride was found to be an effective inhibitor of STAT5 by molecular docking prediction and cellular thermal shift assay.At the cellular level,it can inhibit the proliferation of AML cells at the nanomole level,but has poor inhibitory activity against normal cells,showing good selectivity and safety.Moreover,the concentration gradient inhibited P-STAT5 levels and transcription of STAT5 target genes.Topotecan hydrochloride significantly inhibited AML tumor growth and metastasis at the animal level.The results indicate that topotecan hydrochloride is an effective inhibitor targeting STAT5 to inhibit the growth and survival of AML cells,and is expected to be a safe and effective treatment strategy for patients with AML.Figure [9] Table [1] Reference [49]...