Dataset Information

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

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.

SUBMITTER: Chatterjee A

PROVIDER: S-EPMC4254530 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

Chatterjee Arindam A Cutler Stephen J SJ Doerksen Robert J RJ Khan Ikhlas A IA Williamson John S JS

Bioorganic & medicinal chemistry 20140928 22

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-ba ...[more]

PMID: 25438765

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Project description:Abstract The survival advantage of glioma stem cells (GSCs) represents a critical mechanism for growth, therapy resistance and recurrence in glioblastoma. So far, targeting GSCs has not been highly specific, since these cells co-opt the normal developmental signaling pathways. We have demonstrated that the activated CDK5-CREB1 signaling axis regulates GSC self-renewal and also promotes radiation-resistance. Thus targeting CDK5 signaling is highly rational, yet there are challenges. Most of the available CDK5 inhibitors also target other CDKs non-specifically. In collaboration with The Center for Molecular Evolution and Drug Discovery, we are developing novel CDK5 inhibitors that are highly potent and specific. METHODOLOGY: The CKD5-p25 crystal structure (pdb code 1UNL) was used to conduct a virtual high throughput screen (vHTS). A library of 10 million commercially available compounds which had been filtered to ensure they possessed good drug-like properties was screened against the crystal structure. The top 33 compounds based on their predicted target binding, synthetic feasibility and availability were tested in an in vitro kinase assay to measure CDK5 inhibition. RESULTS: Of the 33 potential hit, 11 compounds showed a CDK5 inhibition of < 50 µM. These 11 hits represent 4 distinct chemical scaffolds. Two of them have IC50 < 1 µM, with one compound having an IC50 < 0.4 µM. The vHTS and subsequent in vitro testing have therefore confirmed the identification of several new series of potent CDK5 hit compounds. We are now characterizing the kinase selectivity of our different hit series and evaluating their activity in cell-based assays. This will help focus efforts on the most promising 1–2 scaffolds for further medicinal chemistry optimization to improve the compounds’ potency, selectivity and brain penetration. Ultimately, our optimized compounds will be tested in GBM models to demonstrate their effectiveness in inhibiting CDK5 as a new approach for treating GBM.

Dataset Information

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

Publications

Discovery of thienoquinolone derivatives as selective and ATP non-competitive CDK5/p25 inhibitors by structure-based virtual screening.

Similar Datasets

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