The Dynamics of Signaling as a Pharmacological Target

• Published in: Cell Vol. 155; no. 2; pp. 448 - 461
• Main Authors: Behar, Marcelo, Barken, Derren, Werner, Shannon L., Hoffmann, Alexander
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-10-2013
• Subjects: Animals; Computer Simulation; cytokines; Drug Discovery; Drug Evaluation, Preclinical; Humans; mathematical models; Molecular Targeted Therapy; NF-kappa B - metabolism; pathogens; pleiotropy; Signal Transduction - drug effects; transcription factor NF-kappa B
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2013.09.018

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.
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•Drugs targeting signaling hubs may block specific dynamic features of the signal•Specific inhibition of dynamic features may introduce pathway selectivity•Phase space analysis reveals principles for drug targeting signaling dynamics•Based on these principles, NFκB dynamics can be manipulated with specificity
Drugs targeting the dynamic features of signaling systems can produce selective effects, making it possible to interfere with specific physiological responses even when the signaling system itself has pleiotropic effects.