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Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based
Arindam Chatterjee1, Stephen J Cutler1, Robert J Doerksen1
1Department of Medicinal Chemistry, School of Pharmacy, University of Mississippi, MS 38677, United States.
Abstract:
Calpain mediated cleavage of CDK5 natural precursor p35 causes a stable complex formation of CDK5/p25, which leads to hyperphosphorylation of tau. Thus inhibition of this complex is a viable target for numerous acute and chronic neurodegenerative diseases involving tau protein, including Alzheimer's disease. Since CDK5 has the highest sequence homology with its mitotic counterpart CDK2, our primary goal was to design selective CDK5/p25 inhibitors targeting neurodegeneration. A novel structure-based virtual screening protocol comprised of e-pharmacophore models and virtual screening workflow was used to identify nine compounds from a commercial database containing 2.84 million compounds. An ATP non-competitive and selective thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with ligand efficiency (LE) of 0.3 was identified as the lead molecule. Further SAR optimization led to the discovery of several low micromolar inhibitors with good selectivity. The research represents a new class of potent ATP non-competitive CDK5/p25 inhibitors with good CDK2/E selectivity.
Insights
Researchers developed novel, selective inhibitors for the CDK5/p25 complex, a key target in neurodegenerative diseases like Alzheimer's. These non-competitive inhibitors show promise for treating tau-related brain disorders.
Area of Science:
- Neuroscience
- Pharmacology
- Biochemistry
Background:
- Calpain cleavage of p35 produces p25, forming a stable CDK5/p25 complex.
- This complex drives tau hyperphosphorylation, a hallmark of neurodegenerative diseases including Alzheimer's disease.
- Targeting the CDK5/p25 complex offers a therapeutic strategy for tauopathies.
Purpose of the Study:
- To design and identify selective inhibitors of the CDK5/p25 complex.
- To develop compounds that specifically target neurodegeneration without affecting the highly homologous CDK2.
- To discover novel ATP non-competitive inhibitors for therapeutic intervention.
Main Methods:
- Employed a structure-based virtual screening protocol.
- Utilized e-pharmacophore models and a virtual screening workflow.
- Screened a database of 2.84 million compounds, followed by Structure-Activity Relationship (SAR) optimization.
Main Results:
- Identified nine potential inhibitor compounds from the virtual screen.
- Discovered a lead thieno[3,2-c]quinolin-4(5H)-one inhibitor (10) with high ligand efficiency.
- Achieved low micromolar inhibitors with significant selectivity for CDK5/p25 over CDK2/E.
Conclusions:
- Developed a new class of potent, ATP non-competitive CDK5/p25 inhibitors.
- Demonstrated good selectivity against CDK2/E, minimizing off-target effects.
- These inhibitors represent a promising therapeutic avenue for neurodegenerative diseases involving tau pathology.
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