title: The dynamics of signaling as a pharmacological target.
abstract: Highly networked signaling hubs are often associated with disease, but targeting them pharmacologically has largely been unsuccessful in the clinic because of their functional pleiotropy. Motivated by the hypothesis that a dynamic signaling code confers functional specificity, we investigated whether dynamic features may be targeted pharmacologically to achieve therapeutic specificity. With a virtual screen, we identified combinations of signaling hub topologies and dynamic signal profiles that are amenable to selective inhibition. Mathematical analysis revealed principles that may guide stimulus-specific inhibition of signaling hubs, even in the absence of detailed mathematical models. Using the NFκB signaling module as a test bed, we identified perturbations that selectively affect the response to cytokines or pathogen components. Together, our results demonstrate that the dynamics of signaling may serve as a pharmacological target, and we reveal principles that delineate the opportunities and constraints of developing stimulus-specific therapeutic agents aimed at pleiotropic signaling hubs.
authors.affiliation: Signaling Systems Laboratory, Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093, USA; San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA; Computational Biosciences Institute, University of California, Los Angeles, Los Angeles, CA 90025, USA; Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90025, USA.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Behar
authors.forename: Derren
authors.initials: D
authors.lastname: Barken
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Werner
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D003198:Computer Simulation; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D058990:Molecular Targeted Therapy; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D016328:NF-kappa B