A new cyclin-dependent kinase-9 inhibitor A09-003 induces apoptosis in acute myeloid leukemia cells with reduction of myeloid cell leukemia sequence-1 protein

Abstract

Acute myeloid leukemia (AML) is the most common type of hematological disease in adults, and has a very poor outcome [1]. Based on its wide range of efficacy in AML models, a small-molecule inhibitor of the anti-apoptotic protein BCL-2, venetoclax (ABT-199/GDC-0199), was developed for clinical trials. However, venetoclax showed limited monotherapy activity [2]. The overexpression of myeloid cell leukemia sequence-1 protein (Mcl-1)—due to mutations in Fms-like tyrosine kinase 3 internal tandem duplication (FLT-3 ITD)—was considered to be the main reason for low efficacy of venetoclax in clinical trials [3-5]. To achieve venetoclax sensitization in AML, targeting CDK-9 with venetoclax is a promising therapeutic strategy.In this study, we developed A09-003 as a potent inhibitor of CDK-9, with an IC50 value of 16 nM. A09-003 inhibited cell proliferation in various leukemia cell lines. In particular, the proliferation inhibitory effect of A09-003 was most potent in MV4-11 and Molm-14 cells, harboring the FLT-3 ITD mutation with a high expression profile of Mcl-1. Marker analysis revealed that A09-003 reduced CDK-9 phosphorylation and reduced RNA polymerase II activity with decreased Mcl-1 expression. Finally, combining A09-003 with venetoclax induced apoptotic cell death in a synergistic manner. In summary, this study shows the potential of A09-003 in AML therapy.