Identification of pyrazole scaffold inhibitors targeting cyclin-dependent kinase 8 for potential use in pulmonary
Tony Eight Lin1, Kai-Cheng Hsu2, Ching-Hsuan Chou3
1Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Abstract:
Idiopathic Pulmonary Fibrosis (IPF) is a disease that includes inflammation and scarring of the lung tissues. Cyclin-dependent kinase 8 (CDK8) is a target of interest due to its role in inflammatory pathways. CDK8 can also modulate the TGF-β/Smad signaling associated with IPF. Herein, a structure-based virtual screening (SBVS) campaign led to the identification of three CDK8 inhibitors. Testing of candidate inhibitors in protein and cellular assays confirmed CDK8 inhibition, with the most potent inhibitor producing an IC50 value of 398.8 nM. Computational analysis identified pharmacological interactions that lead to CDK8 inhibition. No significant cytotoxicity was observed when the inhibitor was treated in vitro. Further results showed that the inhibitor can disrupt proteins associated with the epithelial-mesenchymal transition (EMT) and reduce cell migration. Additionally, the inhibitor can disrupt the TGF- β1/Smad signaling axis in the nucleus, potentially impacting the transcription of IPF related protein expression, when treated in cells at 5 µM. Comparisons to structures of known CDK8 inhibitors showed the identified inhibitor to be structurally novel. When tested against a panel of kinases at 1 µM, the most potent inhibitor demonstrated a favorable CDK8 selectivity profile. The identification of the CDK8 inhibitors in this study can be used in future drug design studies and as CDK8 probes to explore alternative therapeutics for IPF.
Insights
Researchers identified novel Cyclin-dependent kinase 8 (CDK8) inhibitors for Idiopathic Pulmonary Fibrosis (IPF). These compounds show potential therapeutic effects by targeting inflammation and scarring in lung tissues.
Area of Science:
- Pharmacology
- Molecular Biology
- Drug Discovery
Background:
- Idiopathic Pulmonary Fibrosis (IPF) involves lung inflammation and scarring.
- Cyclin-dependent kinase 8 (CDK8) plays a role in inflammatory pathways and TGF-β/Smad signaling relevant to IPF.
Purpose of the Study:
- To identify novel inhibitors of CDK8.
- To evaluate the therapeutic potential of identified CDK8 inhibitors for IPF treatment.
Main Methods:
- Structure-based virtual screening (SBVS) was employed to identify potential CDK8 inhibitors.
- In vitro assays were used to confirm CDK8 inhibition, assess cytotoxicity, and evaluate effects on EMT and TGF-β1/Smad signaling.
Main Results:
- Three novel CDK8 inhibitors were identified, with the most potent exhibiting an IC50 of 398.8 nM.
- The lead inhibitor showed no significant cytotoxicity, disrupted EMT-associated proteins, reduced cell migration, and inhibited TGF-β1/Smad signaling.
- The identified inhibitor demonstrated a favorable CDK8 selectivity profile against other kinases.
Conclusions:
- Novel, structurally unique CDK8 inhibitors were discovered.
- These inhibitors show promise for developing new IPF therapeutics by targeting key disease pathways.
- The identified compounds can serve as valuable probes for further research into CDK8's role in IPF.
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