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

Oncotarget, 2017-05, Vol.8 (20), p.33779-33795

Copyright: © 2017 Rzymski et al. 2017 ;ISSN: 1949-2553 ;EISSN: 1949-2553 ;DOI: 10.18632/oncotarget.16810 ;PMID: 28422713

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Title:
SEL120-34A is a novel CDK8 inhibitor active in AML cells with high levels of serine phosphorylation of STAT1 and STAT5 transactivation domains
Author: Rzymski, Tomasz ; Mikula, Michał ; Żyłkiewicz, Eliza ; Dreas, Agnieszka ; Wiklik, Katarzyna ; Gołas, Aniela ; Wójcik, Katarzyna ; Masiejczyk, Magdalena ; Wróbel, Anna ; Dolata, Izabela ; Kitlińska, Agata ; Statkiewicz, Małgorzata ; Kuklinska, Urszula ; Goryca, Krzysztof ; Sapała, Łukasz ; Grochowska, Aleksandra ; Cabaj, Aleksandra ; Szajewska-Skuta, Małgorzata ; Gabor-Worwa, Ewelina ; Kucwaj, Katarzyna ; Białas, Arkadiusz ; Radzimierski, Adam ; Combik, Michał ; Woyciechowski, Jakub ; Mikulski, Maciej ; Windak, Renata ; Ostrowski, Jerzy ; Brzózka, Krzysztof
Subjects: Animals ; Antineoplastic Agents - chemistry ; Antineoplastic Agents - pharmacology ; Cell Line, Tumor ; Cyclin-Dependent Kinase 8 - antagonists & inhibitors ; Cyclin-Dependent Kinase 8 - chemistry ; Disease Models, Animal ; Gene Expression Profiling ; Gene Expression Regulation, Leukemic - drug effects ; Humans ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Mice ; Models, Molecular ; Molecular Conformation ; Phosphorylation - drug effects ; Protein Binding ; Protein Interaction Domains and Motifs - drug effects ; Protein Kinase Inhibitors - chemistry ; Protein Kinase Inhibitors - pharmacology ; Research Paper ; STAT1 Transcription Factor - chemistry ; STAT1 Transcription Factor - metabolism ; STAT5 Transcription Factor - chemistry ; STAT5 Transcription Factor - metabolism ; Xenograft Model Antitumor Assays
Is Part Of: Oncotarget, 2017-05, Vol.8 (20), p.33779-33795
Description: 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.
Publisher: United States: Impact Journals LLC
Language: English
Identifier: ISSN: 1949-2553
EISSN: 1949-2553
DOI: 10.18632/oncotarget.16810
PMID: 28422713
Source: Geneva Foundation Free Medical Journals
PubMed Central (Open access)
MEDLINE
Alma/SFX Local Collection

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

Copyright: © 2017 Rzymski et al. 2017 ;ISSN: 1949-2553 ;EISSN: 1949-2553 ;DOI: 10.18632/oncotarget.16810 ;PMID: 28422713

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