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Cited by 123Synthesis and biological activityComputational Drug Discovery MethodsWnt/β-catenin signaling in development and cancer

Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening

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Czodrowski, Paul, Mallinger, Aurélie, Wienke, Dirk, Esdar, Christina, Pöschke, Oliver, Busch, Michael, Rohdich, Felix, Eccles, Suzanne A. +10 more·2016·Journal of Medicinal Chemistry
DOI 10.1021/acs.jmedchem.6b00597
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Abstract

The mediator complex-associated cyclin dependent kinase CDK8 regulates β-catenin-dependent transcription following activation of WNT signaling. Multiple lines of evidence suggest CDK8 may act as an oncogene in the development of colorectal cancer. Here we describe the successful optimization of an imidazo-thiadiazole series of CDK8 inhibitors that was identified in a high-throughput screening campaign and further progressed by structure-based design. In several optimization cycles, we improved the microsomal stability, potency, and kinase selectivity. The initial imidazo-thiadiazole scaffold was replaced by a 3-methyl-1H-pyrazolo[3,4-b]-pyridine which resulted in compound 25 (MSC2530818) that displayed excellent kinase selectivity, biochemical and cellular potency, microsomal stability, and is orally bioavailable. Furthermore, we demonstrated modulation of phospho-STAT1, a pharmacodynamic biomarker of CDK8 activity, and tumor growth inhibition in an APC mutant SW620 human colorectal carcinoma xenograft model after oral administration. Compound 25 demonstrated suitable potency and selectivity to progress into preclinical in vivo efficacy and safety studies.

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Crossref · 10.1021/acs.jmedchem.6b00597

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  • CDK8 inhibition by MSC2530818 did not alter the phosphorylation profile of RBP1, indicating the treatment did not affect basal transcriptional programs.

    “CDK8 inhibition by MSC2530818 did not alter the phosphorylation profile of RBP1, suggesting that our treatment did not affect basal transcriptional programs (Sup. Figure 9B)”

    From CDK8 fine-tunes IL-6 transcriptional activities by limiting STAT3 resident time at the gene loci (2020) · cites this paper as Czodrowski et al., 2016

    The Supporting Information summary (p. 1) identifies MSC2530818 as a CDK8 inhibitor, and the compound-characterization passage (p. 8) reports cellular CDK8 activity. Neither passage reports an RBP1 phosphorylation profile or shows that basal transcriptional programs were unaffected; the citing sentence points to its own Supplementary Figure 9B for that observation. (LLM, conf=0.83)

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Authors
Czodrowski, P., Mallinger, A., Wienke, D., Esdar, C., Pöschke, O., Busch, M., Rohdich, F., Eccles, S. A., Ortiz-Ruiz, M.-J., Schneider, R., Raynaud, F. I., Clarke, P. A., Musil, D., Schwarz, D., Dale, T., Urbahns, K., Blagg, J., & Schiemann, K.
Affiliations
  • Merck KGaA, Darmstadt (Germany) (DE)
  • The Institute of Cancer Research , at, at at , , ,
  • Merck KGaA , Frankfurter Strasse 250 , , ,
  • Institute of Cancer Research (GB)
  • Cardiff University (GB)
Corresponding author
  • Czodrowski, Paul
  • Schiemann, Kai
ORCID
Venue
Journal of Medicinal Chemistry
Publisher
American Chemical Society (ACS)
Published
2016-08-04
Volume
59
Issue
20
Pages
9337-9349
ISSN
  • 0022-2623 (ISSN-L)
  • 1520-4804
DOI
10.1021/acs.jmedchem.6b00597
OpenAlex
W2479868564
Cited by
123
References
1
Citations by year
2026: 15 · 2025: 15 · 2024: 11 · 2023: 8 · 2022: 14 · 2021: 11 · 2020: 13 · 2019: 10 · 2018: 12 · 2017: 13 · 2016: 1
FWCI
5.97
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Medicinal Chemistry (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
  • DORA PSI (Paul Scherrer Institute) (submittedVersion, other-oa)
Funders
  • Cancer Research UK (C309/A11566)
  • Royal Marsden NHS Foundation Trust (NA)
Topics
  • Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Keywords
CDK8 inhibitors, CDK8, pyrazolo[3,4-b]pyridines, structure-based drug design, Wnt signaling, colorectal cancer, kinase selectivity, microsomal stability, oral bioavailability, STAT1 phosphorylation, pharmacodynamic biomarkers, tumor growth inhibition
MeSH terms
Animals, Antineoplastic Agents, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Female, Humans, Imidazoles, Mice, Nude, Neoplasms, Experimental, Structure-Activity Relationship, Thiadiazoles, Biomarkers, Tumor, Molecular Structure, Protein Kinase Inhibitors, Cell Proliferation, Mice, Drug Discovery, Cyclin-Dependent Kinase 8, High-Throughput Screening Assays

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