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

Nicolas A. Pabon, Qiuhong Zhang, J. Agustin Cruz, David L. Schipper, Carlos J. Camacho () and Robin E. C. Lee ()
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Nicolas A. Pabon: University of Pittsburgh
Qiuhong Zhang: University of Pittsburgh
J. Agustin Cruz: University of Pittsburgh
David L. Schipper: University of Pittsburgh
Carlos J. Camacho: University of Pittsburgh
Robin E. C. Lee: University of Pittsburgh

Nature Communications, 2019, vol. 10, issue 1, 1-9

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-08802-0

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