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.
MAP kinase-interacting kinases (MNK1 and MNK2) are often activated downstream of ERK and p38 MAPK in the MAP kinase family. The role of MNKs in the development and progression of solid tumors and hematological malignancies has been widely discussed, particularly in the context of cap dependent translation, regulated by phosphorylation of eIF4E. MNK/eIF4E axis is involved in the expression of pro angiogenic, antiapoptotic, cell cycle, and motility proteins, such as MCL1, VEGF, MMP3, SNAIL, SMAD2, β-catenin or cyclin D1, and is essential during Ras and c Myc-induced transformation. MNK1/2 emerged as eligible targets for drug discovery in oncology, based on the antitumor effects observed in genetic knockout and RNA interference experiments and at the same time lack of adverse effects in dual knockout animals. There is a high interest in the development of pharmacological inhibitors of MNK1/2 as not only tools for further basic research studies but also potential drugs in diseases characterized by deregulated translation. Unfortunately, the role of MNK1/2 in cancer still remains elusive due to the absence of potent and selective probes. Moreover, in many instances, hypotheses have been built reliant upon unspecific MNK1/2 inhibitors such as CGP57380 or cercosporamide. Lately, the first two clinical programs targeting MNKs in oncology have been revealed (eFT508 and BAY 1143269), although several other MNK programs are currently running at the preclinical stage. This review aims to provide an overview of recent progress in the development of MNK inhibitors.
CDK8 is a kinase component of the mediator complex which functions as a bridge between a basal transcriptional machinery and specific transcription factors. CDK8 is amplified and differentially expressed in colorectal cancer and in certain hematological malignancies such as mantle cell lymphomas. Cells that express elevated CDK8 levels are highly dependent on its expression for proliferation. Here we report development of first-in-class selective inhibitors CDK8. Compounds from the SEL120 series have binding affinities towards CDK8 in the low nM range. Results from the kinome panel indicated that selectivity of SEL120 compounds was comparable with some of the most selective clinical kinase inhibitors. SEL120 compounds reduced viability of mantle cell lymphoma and colorectal cancer cell lines, with particularly good activity in cell lines overexpressing CDK8 and with G13D mutation in KRAS. Slightly lower sensitivity was observed for cells with mutated P53 and other mutations in KRAS/BRAF pathway. In contrast to pan-CDK inhibitors with main target activity on CDK9, treatment with SEL120 compounds did not repress phosphorylation of PolII and did not cause global transcriptional shutdown. Selective inhibition of CDK8 was sufficient to inhibit both paracrine and autocrine activities of cancer cells and stimulated normal cells. Production of proinflammatory cytokines, such as IL6 was repressed by SEL120 compounds in normal and cancer cells stimulated by sub-optimal doses of chemotherapeutics. SEL120 also reduced both murine and human IL6 in blood of mice bearing human xenograft models. Oral administration of SEL120 revealed favorable pharmacokinetics profile and strong, dose dependent potency in colon cancer mouse xenograft models. Presented data validate inhibition of CDK8 as a promising strategy for anticancer treatment, particularly for CRC and mantle cell lymphomas resistant to current treatments. Citation Format: Tomasz Rzymski, Adrian Zarebski, Renata Windak, Karolina Krawczynska, Ewa Trebacz, Agnieszka Dreas, Katarzyna Kucwaj, Karolina Osowska, Marek Cholody, Paulina Szczepanska, Jakub Woyciechowski, Radosław Obuchowicz, Magdalena Salwińska, Joanna Fogt, Malgorzata Zurawska, Arkadiusz Białas, Katarzyna Wiklik, Mariusz Milik, Angelo Sanzone, Adam Radzimierski, Krzysztof Brzózka. Development of selective CDK8 inhibitors for colorectal cancer and mantle cell lymphoma treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 696. doi:10.1158/1538-7445.AM2013-696
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