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.
Highlights
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
To demonstrate a network-centric strategy for targeting TNFinduced nuclear factor (NF)-κB signaling, we focused on differential gene expression (GE) signatures from the NIH Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 dataset[30]
A compound that disrupts TRADD or TRAF2 in Fig. 1a might have similar signatures to the KD of genes in the pathway such as TNFR1, UBC, or NEMO. We leverage this guilt by association, which suggests that chemical inhibition acts broadly within a signaling subnetwork (Supplementary Fig. 1), to drug the NF-κB signaling pathway
Summary
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. 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. An alternative network-centric strategy is to predict small molecules that act on rate-limiting PPIs in the signaling pathway in silico and screen them for phenotypes associated with pathway disruption in vivo. Complete disruption of IKK and NFκB can have damaging effects on the cell, their dynamics in response to disease-associated inflammatory signals are influenced by >50 other proteins. We find two first-in-class small molecule inhibitors of the pathway that limit PPIs upstream of IKK recruitment and inhibit TNF-induced NF-κB activation. Our results combine to demonstrate a valuable network-centric systems biology approach to drug discovery
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