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

Author

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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)

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.

Suggested Citation

  • Nicolas A. Pabon & Qiuhong Zhang & J. Agustin Cruz & David L. Schipper & Carlos J. Camacho & Robin E. C. Lee, 2019. "A network-centric approach to drugging TNF-induced NF-κB signaling," Nature Communications, Nature, vol. 10(1), pages 1-9, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08802-0
    DOI: 10.1038/s41467-019-08802-0
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