Antileukemic Activity of Ypn-005, a CDK7 Inhibitor, Inducing Apoptosis through c-MYC and FLT3 Suppression in Acute Myeloid Leukemia

Abstract

Background Acute myeloid leukemia (AML) is an aggressive blood cancer with a high rate of relapse associated with adverse survival outcomes, especially in elderly patients. An aberrant expression of cyclin-dependent kinase 7 (CDK7) is associated with poor outcomes and CDK7 inhibition has showed antitumor activities in various cancers. In this study, we explored the potential efficacy of YPN-005, a highly selective CDK7 inhibitor, and evaluated a possible mechanism of the antileukemic effect of YPN-005 in vitro, in vivo, and ex vivo AML models. Methods We investigated the efficacy of YPN-005 in AML cell lines, xenograft mouse model, and primary AML cells. The anti-proliferative effect of YPN-005 was measured by cell viability assay using CellTiter-Glo assay, and the apoptotic level was evaluated using Annexin V/PI staining. The phosphorylation of RNA polymerase II, c-MYC, MCL1, and phosphorylated FLT3/STAT5 protein expression was measured using an immunoblotting assay. To reveal the anti-leukemic effect of YPN-005 on AML cells in vivo, we observed tumor load using the IVIS spectrum in vivo imaging system (PerkinElmer) in an orthotopic mouse model using pGFP-transduced MOLM-13 cell line. Results YPN-005 effectively inhibited the proliferation of AML cells by inducing apoptosis and reducing phosphorylation of RNA polymerase II. The c-MYC protein expression decreased with the treatment of YPN-005 (Figure 1.), and the effect of YPN-005 was negatively correlated with c-myc expression. YPN-005 also showed antileukemic activities in primary AML cells, especially those harboring FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutation and in in vivo mouse model (Figure 2.). Phosphorylated FLT3/STAT5 was decreased and FLT3/STAT5 was downregulated with YPN-005 treatment. Conclusion In conclusion, our data suggest that YPN-005, a CDK7 inhibitor has a potential role in treating AML by inducing apoptosis and suppressing c-MYC and FLT3/STAT5. The antileukemic property of YPN-005 needs to be further evaluated in FLT3-mutated AML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal