SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains.

Tomasz Rzymski,Krzysztof Brzózka,Aniela Gołas,Katarzyna Wójcik,Katarzyna Kucwaj,Eliza Żyłkiewicz,Maciej Mikulski,Michał Mikula,Urszula Kuklinska,Ewelina Gabor-Worwa,Aleksandra Cabaj,Agnieszka Dreas,Jerzy Ostrowski,Renata Windak,Michał Combik,Łukasz Sapała,Agata Kitlińska,Anna Wróbel,Magdalena Masiejczyk,Jakub Woyciechowski,Małgorzata Statkiewicz,Adam Radzimierski,Krzysztof Goryca,Małgorzata Szajewska-Skuta,Aleksandra Grochowska,Arkadiusz Białas,Izabela Dolata,Katarzyna Wiklik

doi:10.18632/oncotarget.16810

Abstract

Inhibition of oncogenic transcriptional programs is a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by associating with the Mediator complex. X-ray crystallography has shown SEL120-34A to be a type I inhibitor forming halogen bonds with the protein's hinge region and hydrophobic complementarities within its front pocket. SEL120-34A inhibits phosphorylation of STAT1 S727 and STAT5 S726 in cancer cells in vitro. Consistently, regulation of STATs- and NUP98-HOXA9- dependent transcription has been observed as a dominant mechanism of action in vivo. Treatment with the compound resulted in a differential efficacy on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In contrast, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo efficacy in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety and in vivo efficacy provide a rationale for the further clinical development of SEL120-34A as a personalized therapeutic approach in AML.

Highlights

Two paralog kinases: Cyclin-dependent kinase 8 (CDK8) and CDK19, reversibly associate with the Mediator complex and form its key regulatory unit [1, 2]
We determined that SEL120-34A inhibited kinase activities of CDK8/CycC and CDK19/CycC complexes with an IC50 of 4.4 nM and 10.4 nM, respectively (Figure 1B)
Efficacy of pharmacological inhibition of CDK8 on cancer cells. Our studies and those of other groups indicated moderate or low activity of known CDK8 inhibitors on com/oncotarget cancer (CRC) cell lines in vitro, we have focused on leukemia cells which were found to be sensitive to Cortistatin A (CA) [4]

Summary

Introduction

Two paralog kinases: CDK8 and CDK19, reversibly associate with the Mediator complex and form its key regulatory unit [1, 2]. Effects of CA on RNA polymerase II (RNAP II) transcription in the HCT-116 CRC line were rather modest and involved genes implicated in inflammation, growth, and metabolic regulation [6]. These effects only partially overlap with transcriptional profiling of CDK8 and CDK19 knockdown cells and the response to CA in AML cells [12, 15]. Such discrepancies were further discussed as a result of differences between kinase and scaffolding functions of CDK8 and CDK19 within the Mediator complexes [6]

Methods

Results

Conclusion