SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains
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Tomasz Rzymski1,*, Michał Mikula2,*, Eliza Żyłkiewicz1, Agnieszka Dreas1, Katarzyna Wiklik1, Aniela Gołas1, Katarzyna Wójcik1, Magdalena Masiejczyk1, Anna Wróbel1, Izabela Dolata1, Agata Kitlińska1, Małgorzata Statkiewicz2, Urszula Kuklinska2, Krzysztof Goryca2, Łukasz Sapała1, Aleksandra Grochowska3, Aleksandra Cabaj2,4, Małgorzata Szajewska-Skuta1, Ewelina Gabor-Worwa1, Katarzyna Kucwaj1, Arkadiusz Białas1, Adam Radzimierski1, Michał Combik1, Jakub Woyciechowski1, Maciej Mikulski1, Renata Windak1, Jerzy Ostrowski2,3 and Krzysztof Brzózka1
1R&D Department, Selvita S.A., Kraków, Poland
2Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland
3Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland
4Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Warsaw, Poland
*These authors have contributed equally to this work
Krzysztof Brzózka, email: firstname.lastname@example.org
Keywords: CDK8 mediator, kinase inhibitor, STAT5, AML, leukemia stem cells
Received: August 04, 2016 Accepted: March 09, 2017 Published: April 04, 2017
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.
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