The dynamics of signaling as a pharmacological target.

TitleThe dynamics of signaling as a pharmacological target.
Publication TypeJournal Article
Year of Publication2013
AuthorsBehar M, Barken D, Werner SL, Hoffmann A
JournalCell
Volume155
Issue2
Pagination448-61
Date Published2013 Oct 10
ISSN1097-4172
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.

DOI10.1016/j.cell.2013.09.018
PubMed URLhttp://www.ncbi.nlm.nih.gov/pubmed/24120141?dopt=Abstract
PMCPMC3856316
Alternate JournalCell
PubMed ID24120141