Résumé
For decades, drug discovery mainly focused on the activation and inhibition of protein functions through the development of small molecules fitting into enzyme and receptor pockets. Although successful, this strategy cannot be applied to all biological targets, including proteins without enzymatic activity or proteins that function via protein-protein interaction (PPIs). At the end of the 20th century, there has been an emergence of new classes of therapeutics including biologics (in particular antibodies) and siRNA. Despite undeniable advantages, such molecules can present some drawbacks, such as size, ability to cross the cell membrane for targeting intracellular proteins, stability, delivery and off-target issues. Here, we present some alternative strategies to these molecules to develop drug candidates able to modulate non-conventional proteins involved in cancer, and for which an antagonist/inhibitor has not been identified yet. The first strategy concerns the design of specific therapeutic tools based on the stapled peptide technology for inhibiting PPI interactions, which are essential to target protein functions.1 The second strategy is based on the use of the proteolysis-targeting chimeras (PROTAC) technology to trigger the target protein for degradation.2