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 1, Michał Mikula 2, Eliza Żyłkiewicz 1, Agnieszka Dreas 1, Katarzyna Wiklik 1, Aniela Gołas 1, Katarzyna Wójcik 1, Magdalena Masiejczyk 1, Anna Wróbel 1, Izabela Dolata 1, Agata Kitlińska 1, Małgorzata Statkiewicz 2, Urszula Kuklinska 2, Krzysztof Goryca 2, Łukasz Sapała 1, Aleksandra Grochowska 3, Aleksandra Cabaj 2 4, Małgorzata Szajewska-Skuta 1, Ewelina Gabor-Worwa 1, Katarzyna Kucwaj 1, Arkadiusz Białas 1, Adam Radzimierski 1, Michał Combik 1, Jakub Woyciechowski 1, Maciej Mikulski 1, Renata Windak 1, Jerzy Ostrowski 2 3, Krzysztof Brzózka 1
Inhibition of oncogenic transcriptional programs is really a promising therapeutic strategy. A substituted tricyclic benzimidazole, SEL120-34A, is really a novel inhibitor of Cyclin-dependent kinase 8 (CDK8), which regulates transcription by connecting using the Mediator complex. X-ray crystallography has proven SEL120-34A to become a type I inhibitor developing halogen bonds using 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, regulating STATs- and NUP98-HOXA9- dependent transcription continues to be observed like a dominant mechanism of action in vivo. Treatment using the compound led to a differential effectiveness on AML cells with elevated STAT5 S726 levels and stem cell characteristics. In comparison, resistant cells were negative for activated STAT5 and revealed lineage commitment. In vivo effectiveness in xenotransplanted AML models correlated with significant repression of STAT5 S726. Favorable pharmacokinetics, confirmed safety as well as in vivo effectiveness give a rationale for that further clinical growth and development of SEL120-34A like a personalized therapeutic approach in AML.SEL120