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Cell-based assays for protein-protein interactions
22 October 2013 • Author(s): Mark Wade, Center for Genomic Science of [email protected]
Protein-protein interactions (PPI) form the backbone of all cellular signalling networks, and aberrant PPI contribute to the pathology of several diseases. Thus, strategies to identify PPI modulators are expected to be therapeutically beneficial. However, there are very few examples of clinically approved PPI modulators, reflecting the difficulties of identifying effective compounds for this target class. This perspective reviews the challenges associated with targeting PPI, and summarises the major strategies used to detect and disrupt PPI, with a particular focus on cell-based assays for PPI.
‘Conventional’ targets versus PPI
To date, enzymes and G protein-coupled receptors (GPCRs) are the protein classes on which most drug discovery efforts have been focused. In addition to the sine qua non of target validation, several other factors ensured that these proteins commanded the attention of pharmaceutical companies. Enzymes have well-defined and relatively ‘compact’ catalytic pockets, making them amenable to inhibition with small molecules. Additionally, enzymatic activity facilitates the design of in vitro biochemical assays for small molecule antagonists. Similarly, based on the discovery of binding pockets for the small endogenous ligands on GPCRs, many small molecule modulators of receptor activity have been identified. In both cases, this greatly aids the iterative structure-function analysis process as medicinal chemists seek to improve both potency and selectivity / specificity for the target.
The huge emphasis on small molecule antagonists in these areas, combined with intense competition for market share between companies, means other disease-relevant target classes have perhaps been neglected. Among these, it is clear that PPI represent an opportunity for drug discovery. For example, in cancer, the oncogenic effects of the MYC and NOTCH transcription factors and the MDM2 and WNT oncogenes are mediated via PPI1-4. Furthermore, current estimates suggest there are between 130,000 and 600,000 human PPI compared to ~22,000 individual proteins, offering the potential for very selective targeting of signalling nodes in diverse pathways5,6.
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