Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by
Paul Czodrowski1, Aurélie Mallinger2, Dirk Wienke1
1Merck KGaA , Frankfurter Strasse 250, Darmstadt, 64293, Germany.
Journal of Medicinal Chemistry
|August 5, 2016
Summary
Researchers optimized CDK8 inhibitors for colorectal cancer therapy. Compound 25, a novel pyrazolo-pyridine derivative, shows potent inhibition, selectivity, and oral bioavailability, with promising in vivo efficacy.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Cyclin-dependent kinase 8 (CDK8) regulates WNT signaling and is implicated as an oncogene in colorectal cancer.
- Targeting CDK8 offers a potential therapeutic strategy for colorectal cancer treatment.
Purpose of the Study:
- To optimize a series of imidazo-thiadiazole CDK8 inhibitors identified via high-throughput screening.
- To develop a potent, selective, and orally bioavailable CDK8 inhibitor for colorectal cancer therapy.
Main Methods:
- Structure-based drug design and iterative optimization of an imidazo-thiadiazole scaffold.
- Biochemical and cellular assays to assess kinase selectivity, potency, and microsomal stability.
- In vivo studies using a human colorectal carcinoma xenograft model to evaluate pharmacodynamic effects and tumor growth inhibition.
Main Results:
- Optimization led to the replacement of the initial scaffold with a 3-methyl-1H-pyrazolo[3,4-b]-pyridine core, yielding compound 25 (MSC2530818).
- Compound 25 exhibited excellent kinase selectivity, potent biochemical and cellular activity, improved microsomal stability, and oral bioavailability.
- Oral administration of compound 25 modulated phospho-STAT1 (a pharmacodynamic biomarker) and inhibited tumor growth in an APC mutant SW620 xenograft model.
Conclusions:
- Compound 25 represents a highly optimized CDK8 inhibitor with significant potential for further preclinical development.
- The developed compound demonstrates promising efficacy and selectivity, warranting progression into in vivo efficacy and safety studies for colorectal cancer treatment.
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