1. SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains
- Author
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Łukasz Sapała, Ewelina Gabor-Worwa, Adam Radzimierski, Krzysztof Goryca, Anna Wrobel, Magdalena Masiejczyk, Katarzyna Kucwaj, Aleksandra Cabaj, Małgorzata Szajewska-Skuta, Maciej Mikulski, Eliza Żyłkiewicz, Michal Combik, Jerzy Ostrowski, Izabela Dolata, Agnieszka Dreas, Jakub Woyciechowski, Krzysztof Brzózka, Urszula Kuklinska, Renata Windak, Malgorzata Statkiewicz, Aleksandra Grochowska, Michal Mikula, Arkadiusz Białas, Katarzyna Wojcik, Katarzyna Wiklik, Agata Kitlińska, Tomasz Rzymski, and Aniela Golas
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0301 basic medicine ,Models, Molecular ,Myeloid ,kinase inhibitor ,Molecular Conformation ,Antineoplastic Agents ,03 medical and health sciences ,Transactivation ,Mice ,AML ,Cell Line, Tumor ,STAT5 Transcription Factor ,Medicine ,Animals ,Humans ,Protein Interaction Domains and Motifs ,STAT1 ,CDK8 mediator ,Phosphorylation ,Protein Kinase Inhibitors ,STAT5 ,biology ,business.industry ,Kinase ,Gene Expression Regulation, Leukemic ,Gene Expression Profiling ,leukemia stem cells ,Cyclin-Dependent Kinase 8 ,Xenograft Model Antitumor Assays ,Disease Models, Animal ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,STAT1 Transcription Factor ,Oncology ,Cancer cell ,Immunology ,Cancer research ,biology.protein ,Cyclin-dependent kinase 8 ,Stem cell ,business ,Research Paper ,Protein Binding - Abstract
// Tomasz Rzymski 1, * , Michal Mikula 2, * , Eliza Żylkiewicz 1 , Agnieszka Dreas 1 , Katarzyna Wiklik 1 , Aniela Golas 1 , Katarzyna Wojcik 1 , Magdalena Masiejczyk 1 , Anna Wrobel 1 , Izabela Dolata 1 , Agata Kitlinska 1 , Malgorzata Statkiewicz 2 , Urszula Kuklinska 2 , Krzysztof Goryca 2 , Łukasz Sapala 1 , Aleksandra Grochowska 3 , Aleksandra Cabaj 2, 4 , Malgorzata Szajewska-Skuta 1 , Ewelina Gabor-Worwa 1 , Katarzyna Kucwaj 1 , Arkadiusz Bialas 1 , Adam Radzimierski 1 , Michal Combik 1 , Jakub Woyciechowski 1 , Maciej Mikulski 1 , Renata Windak 1 , Jerzy Ostrowski 2, 3 and Krzysztof Brzozka 1 1 R&D Department, Selvita S.A., Krakow, Poland 2 Department of Genetics, Maria Sklodowska-Curie Memorial Cancer Center, Warsaw, Poland 3 Department of Gastroenterology, Hepatology and Clinical Oncology, Medical Center for Postgraduate Education, Warsaw, Poland 4 Laboratory of Bioinformatics, Nencki Institute of Experimental Biology, Warsaw, Poland * These authors have contributed equally to this work Correspondence to: Krzysztof Brzozka, email: krzysztof.brzozka@selvita.com Keywords: CDK8 mediator, kinase inhibitor, STAT5, AML, leukemia stem cells Received: August 04, 2016 Accepted: March 09, 2017 Published: April 04, 2017 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.
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- 2017