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 Communjournal_title
Nature communicationsauthors
Pabon NA,Zhang Q,Cruz JA,Schipper DL,Camacho CJ,Lee RECdoi
10.1038/s41467-019-08802-0subject
Has Abstractpub_date
2019-02-26 00:00:00pages
860issue
1issn
2041-1723pii
10.1038/s41467-019-08802-0journal_volume
10pub_type
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