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.
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.
Insights
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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