Abstract 696: Development of selective CDK8 inhibitors for colorectal cancer and mantle cell lymphoma treatment.

Abstract

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

Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19

“…8-(3-(3-Amino-1H-indazol-6-yl)-5-chloropyridin-4-yl)-2,8diazaspiro [4.5]decan-1-one (25). 8-(3-Bromo-5-chloropyridin-4yl)-2,8-diazaspiro [4.5]decan-1-one 27 8 (92% pure, 180 mg, 0.480 mmol) and (3-amino-1H-indazol-6-yl)boronic acid hydrochloride 16 (95% pure, 162 mg, 0.720 mmol) were dissolved in acetonitrile (8 mL), and 0.5 M sodium carbonate in water (2.8 mL, 1.4 mmol) and Pd(dppf)Cl 2 •CH 2 Cl 2 (20 mg, 0.020 mmol) were added.…”

Scalable Synthesis of Acridinium Catalysts for Photoredox Deuterations

“…The former preparation of reagents 3 and 4 for the C-N cross coupling proved challenging during scale-up and led us to circumvent the Sandmeyer iodination from 3 to 4. 8 Gratifyingly, an alternative route consisting of a reductive amination, a Finkelstein reaction, and bromination allowed us to access intermediate 4 in good to excellent yields without any column chromatography. 9 A careful optimization of the nitration and reduction conditions delivered intermediate 3 in good yield, purified by recrystallization.…”