A fragment-based approach to identify protein-protein interaction inhibitors of Shelterin complex assembly

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The ends of our linear chromosomes, the telomeres, are decorated by a multi-protein complex known as Shelterin. The Shelterin complex protects telomeres, which resemble DNA breaks, by averting an illicit telomeric DNA damage response which would threaten genomic integrity. The Shelterin complex further participates in regulating telomere length. This project aims to take the first steps in developing novel chemical tools to probe the function of Shelterin complex components. Specifically, the project will identify small molecule fragments that bind to globular domains in components of the Shelterin complex, using a combination of differential scanning fluorimetry and ligand-observed NMR methods. Fragment binding will be validated by orthogonal biophysical techniques, and the fragment binding sites located and characterised in detail using protein-observed NMR and, if possible, X-ray crystallography. The fragment-protein interaction affinities for the hits will be measured using protein-observed NMR and ITC, and early structure-activity relationship studies will be carried out by purchase or chemical synthesis of close analogues. The results of this study will be a well-understood series of fragment binders suitable for progression through medicinal chemistry to develop potent inhibitors of the protein-protein interactions in the Shelterin complex, as tool compounds to probe the roles of Shelterin in telomere biology.

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www.icr.ac.uk/our-research/researchers-and-teams/professor-ian-collins
www.icr.ac.uk/our-research/researchers-and-teams/sebastian-guettler
www.sguettlerlab.org

Chemical biology
Fragment screening
Protein-protein interactions
Biophysics
Protein biochemistry
Structural biology