First BRET‐based screening assay performed in budding yeast leads to the discovery of CDK5/p25 interaction inhibitors
Abstract
The protein kinase CDK5 (cyclin‐dependent kinase 5) is activated through its association with a cyclin‐like protein p35 or p39. In pathological conditions (such as Alzheimer's disease and various other neuropathies), truncation of p35 leads to the appearance of the p25 protein. The interaction of p25 with CDK5 up‐regulates the kinase activity and modifies the substrate specificity. ATP‐mimetic inhibitors of CDK5 have already been developed. However, the lack of selectivity of such inhibitors is often a matter of concern. An alternative approach can be used to identify highly specific inhibitors that disrupt protein interactions involving protein kinases. We have developed a bioluminescence resonance energy transfer (BRET)‐based screening assay in yeast to discover protein–protein interaction inhibitors (P2I2). Here, we present the first use of BRET in yeast for the screening of small molecule libraries. This screening campaign led to the discovery of one molecule that prevents the interaction between CDK5 and p25, thus inhibiting the protein kinase activity. This molecule may give rise to high‐specificity drug candidates. Accompanying article Zhang et al.
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- Authors
- Corbel, C., Wang, Q., Bousserouel, H., Hamdi, A., Zhang, B., Lozach, O., Ferandin, Y., Tan, V. B. C., Guéritte, F., Colas, P., Couturier, C., & Bach, S.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- North China Electric Power University (CN)
- National University of Singapore (SG)
- Corresponding author
- Bach, Stéphane
- ORCID
- Venue
- Biotechnology Journal
- Publisher
- Wiley
- Published
- 2011-06-16
- Volume
- 6
- Issue
- 7
- Pages
- 860-870
- ISSN
- 1860-6768 (ISSN-L)
- 1860-7314
- OpenAlex
- W2059547847
- Cited by
- 35
- References
- 44
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 3 · 2021: 1 · 2020: 3 · 2019: 2 · 2018: 5 · 2017: 2 · 2016: 3 · 2015: 4 · 2014: 5 · 2012: 3
- FWCI
- 1.30
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Biotechnology Journal (publishedVersion)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- HAL (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › bioluminescence and chemiluminescence research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Advanced Fluorescence Microscopy Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- cyclin-dependent kinase 5, p25, protein-protein interaction inhibitors, bioluminescence resonance energy transfer, yeast-based screening, small molecule library, protein kinase inhibitors, Alzheimer's disease, kinase substrate specificity
- MeSH terms
- Androstanols, HeLa Cells, Humans, Luminescent Proteins, Nerve Tissue Proteins, Protein Binding, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Fluorescence Resonance Energy Transfer, Cyclin-Dependent Kinase 5, Small Molecule Libraries, Drug Discovery, Molecular Dynamics Simulation
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