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Covalent fragment screening in cell-based phenotypic models of disease: a collaborative approach

The application of chemical perturbation approaches in phenotypic models is often used to identify protein targets for therapeutic discovery. Increasingly, small molecule fragments which covalently bind to their protein targets are being used to explore the druggable proteome and the resulting fragment‑protein interactions are characterised by chemoproteomic techniques. In this article, researchers from the Francis Crick Institute (Crick) and GlaxoSmithKline (GSK) outline a new collaborative initiative with the aim to establish a Systems Chemical Biology platform that enables covalent fragment library screening in phenotypic models of human disease, along with chemoproteomic annotation of the fragment library members to enable rapid tool molecule generation for tractable targets.

Fragment screening

Target selection and small molecule screens

The identification of tractable protein targets for efficacious therapeutic intervention is one of the most significant challenges in the discovery of novel medicines. Evidence that therapeutics which target proteins with strong genetic linkage to disease are more likely to be successful in the clinic1,2 has accelerated investment in genome‑wide association studies (GWAS) and large‑scale computational analyses. Genetic perturbation studies (eg, siRNA, shRNA or CRISPR‑Cas9 gene knockdown) in phenotypic models of disease provide further opportunity to link gene products to disease pathways.3 Ultimately, however, the targets identified through these studies need to prove tractable for modulation by a therapeutic molecule.












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