Resumen de Chapter Fifteen - Targeting Protein–Protein Interactions to Treat Cancer—Recent Progress and Future Directions
William Garland, Robert Benezra, Jaideep Chaudhary
Abstract Protein complexes in the interactome provide practical targets for oncology drug discovery. A handful of recent clinical candidates address protein–protein interactions (PPIs) important to the growth/spread of cancer. The list of “tractable protein–protein targets” is growing. With so many cancer targets in the interactome, thoughtful selection of targets amenable to modulation has become a critical task. The effort to find inhibitors or stabilizers of the selected PPI will require careful analysis of the relevant protein surfaces and an early decision on whether to pursue orthosteric and/or allosteric modulators. Computational docking, original design from “hot spot” considerations, or traditional library screening can be used to search for leads. Compounds providing successful orthosteric modulation of PPIs will likely possess larger MW with multiple, low-energy binding sites relative to modulators of traditional targets like protein kinase, GPCR, enzyme, etc., to encompass the larger and less deeply pocketed surface area associated with the typical PPI.
