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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Pabon NA,Zhang Q,Cruz JA,Schipper DL,Camacho CJ,Lee REC

doi

10.1038/s41467-019-08802-0

subject

Has Abstract

pub_date

2019-02-26 00:00:00

pages

860

issue

1

issn

2041-1723

pii

10.1038/s41467-019-08802-0

journal_volume

10

pub_type

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