Enhanced interrogation: emerging strategies for cell signaling inhibition

Abstract

Here we summarize recent and developing chemical approaches for modulating signaling pathways. In particular, we discuss targeting mutant signaling proteins, disrupting protein-protein interactions in cellular signaling networks, designing bivalent inhibitors of signaling proteins and identifying allosteric regulators of signaling enzymes. Over the past decade, great progress in the harvesting of chemical tools for basic research and clinical medicine has been made, but many challenges remain, and examples of exciting future targets are highlighted.

Figure 1

Strategies for targeting signaling pathways. (a) Hyperactive mutant proteins can be inhibited by small molecules that target the active site. Loss–of-function mutations can be rescued by small molecules that complement the mutant protein. (b) The downstream effects of certain protein-protein interactions can be interrupted by synthetic molecules. A and B are two interacting proteins. (c) Inhibition of signaling proteins by bivalent ligands. (d) Allosteric inhibitor induces conformational changes remotely that disrupt ligand binding.