Recent advances in molecular biology of tumors led to novel innovative therapies. Targeted therapies block the development of cancer by interfering with specific molecules involved in carcinogenesis and have shown a great promise in preclinical and clinical settings. Application of anti-EGFR antibodies for the treatment of colorectal cancer (CRC) is a good example of such an approach. EGFR receptor is commonly amplified and promotes tumorigenesis and tumor progression of CRC. The presence of activating KRAS mutations has been identified as a potent predictor of resistance to EGFR-directed antibodies. These agents should therefore be applied only in tumors with a wild-type status of the KRAS.

There are very few therapeutic options for patients resistant to anti-EGFR antibodies with activating mutations in KRAS. SEL120 is a series of small molecule inhibitors of cyclin-dependent kinases CDK8 and CDK9, with high and selective cytotoxicity towards CRC cells with mutated KRAS. Both CDK8 and CDK9 phosphorylate RNA polymerase II (Pol II) and regulate gene expression programs during oncogenic transformation and progression of CRC.  CDK8 is a colon cancer oncogene necessary for b-catenin activity which is deregulated in over 90% of CRC cases. Moreover it was shown that expression of CDK8 significantly increased colon cancer-specific mortality what correlated with CDK8 copy number gain and high activity of b-catenin. CDK9 is frequently induced during oncogenic transformation and is activated by RAS/RAF/MEK pathway and stress. Inhibition of CDK9 plays a crucial role in compounds originally developed as CDK2/4/6-specific cell cycle inhibitors.

Here we report development of selective, ATP- competitive inhibitors of CDK8/9. Compounds from the SEL120 series have binding affinities towards CDK8/9 kinases in the low nM range. Results from the kinome screen (299 kinases) indicated that selectivity of SEL120 compounds was comparable with some of the most selective clinical kinase inhibitors. In addition, several compounds in the series exerted also significant activity on the mitotic kinase Haspin, what could be potentially beneficial for lowering proliferation rate and stabilization of aggressive forms of CRC.

SEL120 compounds inhibited proliferation and clonogenic survival of a number of CRC tumor cell lines, with particularly good activity in CRC cell lines with G13D mutation in KRAS. Slightly lower sensitivity was observed for cells with mutated P53 and other mutations in KRAS/BRAF pathway. Treatment with SEL120 compounds repressed also phosphorylation of Pol II and reduced levels of anti-apoptotic protein Mcl-1 and survival of cancer cells, due to inhibition of CDK8/9 kinases. Furthermore, co-administration of SEL120 compounds with Oxaliplatin, the standard of care in CRC, resulted in strong synergistic cytostatic effects. Oral administration of SEL120 revealed favorable pharmacokinetics profile and strong, dose dependent potency in the HCT116 colon cancer mouse xenograft model, with observed tumor growth inhibition around 80%. Notably, even high doses were safe as tested by blood biochemistry, blood morphology, limited body weight loss and lack of visible histopathological changes in major organs. Presented data validate inhibition of CDK8 and CDK9 as a promising strategy for anticancer treatment, particularly for solid tumors such as CRC resistant to current therapies.

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