Compound #41 Targets Acute Myelogenous Leukemia by Inhibiting the Wnt/β-catenin Signaling Pathway

Background/Aim: Aberrant activation of the Wnt//3- catenin signaling pathway contributes to the pathogenesis acute myelogenous leukemia (AML). Thus, targeting this pathway offers a promising therapeutic strategy against AML. Here, we synthesized a novel dipeptide-type inhibitor of the Wnt//3-catenin signaling pathway, compound #41, and explored its anti-tumor effects on AML cells. Materials and Methods: We evaluated the inhibitory effect of compound #41 on T cell factor (TCF)//3-catenin transcriptional activity using a luciferase (Luc) reporter assay. The anti-tumor effects were assessed on KG1a and MV4;11 human AML cells using RT-qPCR, western blotting, and WST-8, cell cycle, and apoptosis assays. Differentially expressed genes were analyzed by RNA sequencing (RNA-seq). Additionally, we investigated the in vivo effects of compound #41 using KG1a-Luc/GFP cells in orthotopic mouse model. Results: The Luc reporter assay showed that compound #41 decreased the TCF//3-catenin transcriptional activity. Compound #41 blocked the cell cycle progression, inhibited cell proliferation, and induced apoptosis in AML cells. Treatment with compound #41 down-regulated the expression of /3-catenin, Survivin, and /3-catenin-specific target genes, as demonstrated by RNA-seq. In vivo analysis showed that compound #41 blocked the expansion of KG1a-Luc/GFP cells in the bone marrow and prolonged the overall survival KG1a-Luc/GFP-transplanted mice. Conclusion: Compound #41 suppressed the Wnt//3-catenin signaling pathway by reducing CTNNB1 levels and induced apoptosis in AML cells. Furthermore, compound #41 inhibited the proliferation of KG1a-Luc/GFP cells in the bone marrow and extended the overall survival of mice. Thus, compound #41 is an attractive Wnt//3-catenin signaling pathway inhibitor of AML.