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

Nature Communications
Nicolas A PabonRobin E C Lee

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.

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Citations

Mar 10, 2020·PLoS Computational Biology·Sanjana GuptaJames R Faeder
Dec 20, 2019·BioEssays : News and Reviews in Molecular, Cellular and Developmental Biology·Louis GauthierStephen W Michnick
Aug 25, 2020·Science Advances·Abhirup MandalSamir Mitragotri
Dec 19, 2020·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Jinfu QianGuang Liang
Aug 30, 2021·European Journal of Pharmacology·Mingyan ShaoYong Wang
Feb 1, 2022·The Biochemical Journal·Masatoshi Haga, Mariko Okada

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Datasets Mentioned

BETA
GSE70138
GSE92742

Methods Mentioned

BETA
gene knockdown
nuclear translocation
ubiquitination
thermal shift
PCR
transfection
Profiler

Software Mentioned

smina
FTMap
MATLAB
GeneArt
Cell Profiler
BioGrid
ImageJ
Molport

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