title: Using small molecules and chemical genetics to interrogate signaling networks.
abstract: The limited clinical success of therapeutics targeting cellular signaling processes is due to multiple factors, including off-target effects and complex feedback regulation encoded within the signaling network. To understand these effects, chemical proteomics and chemical genetics tools have been developed to map the direct targets of kinase inhibitors, determine the network-level response to inhibitor treatment, and to infer network topology. Here we provide an overview of chemical phosphoproteomic and chemical genetic methods, including specific examples where these methods have been applied to yield biological insight regarding network structure and the system-wide effects of targeted therapeutics. The challenges and caveats associated with each method are described, along with approaches being used to resolve some of these issues. With the broad array of available techniques the next decade should see a rapid improvement in our understanding of signaling networks regulation and response to targeted perturbations, leading to more efficacious therapeutic strategies.
authors.affiliation: Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, 02139, United States.
authors.forename: Scott M
authors.initials: SM
authors.lastname: Carlson
authors.forename: Forest M
authors.initials: FM
authors.lastname: White
mesh_terms: D016503:Drug Delivery Systems; D008967:Molecular Biology / Q000379:methods*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D040901:Proteomics / Q000379:methods*; D015398:Signal Transduction / Q000502:physiology*; D054852:Small Molecule Libraries
chemical_list: D054852:Small Molecule Libraries