A network-centric approach to drugging TNF-induced NF-κB signaling

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.