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- Title
A network-centric approach to drugging TNF-induced NF-κB signaling.
- Authors
Pabon, Nicolas A.; Zhang, Qiuhong; Cruz, J. Agustin; Schipper, David L.; Camacho, Carlos J.; Lee, Robin E. C.
- Abstract
Target-centric drug development strategies prioritize single-target potency in vitro and do not account for connectivity and multi-target effects within a signal transduction network. Here, we present a systems biology approach that combines transcriptomic and structural analyses with live-cell imaging to predict small molecule inhibitors of TNF-induced NF-κB signaling and elucidate the network response. We identify two first-in-class small molecules that inhibit the NF-κB signaling pathway by preventing the maturation of a rate-limiting multiprotein complex necessary for IKK activation. Our findings suggest that a network-centric drug discovery approach is a promising strategy to evaluate the impact of pharmacologic intervention in signaling. Chemical perturbation of specific protein-protein interactions is notoriously difficult, yet necessary when complete inhibition of a signalling pathway is detrimental to the cell. Here, the authors use a systems approach and identify two first-in-class small molecules that specifically inhibit TNF-induced NF-κB activation.
- Publication
Nature Communications, 2019, Vol 10, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-019-08802-0