Researchers from The University of Pittsburgh have identified small molecules to specifically inhibit tumor necrosis factor (TNF) induced Nuclear Factor κB (NF-κB) inflammatory pathways.
Description
Using a novel systems biology approach combining transcriptomics and structural analysis with live-cell imaging, two first-in-class protein-protein inhibitors (PPIs) have been identified and shown to selectively inhibit TNF-induced NF-κB inflammatory pathways. Selective inhibition of these pathways has the potential to reduce off-target impacts and preserve other vital processes in the NF-κB signaling pathway. Additionally, this network-centric drug discovery approach could identify other selective pathway inhibition drugs in other diseases.
Applications
1. Targeting inflammatory pathways
2. Novel drug discovery approaches
Advantages
Current approaches to drug discovery focus on single targets and neglect to consider multi-target effects and connectivity within a signal transduction network. Given most cellular behavior is regulated by complex networks of protein interactions, inhibition of one step can lead to inhibition of a complete signaling pathway, resulting in side effects downstream and even cell toxicity.
This novel network-centric approach is designed to explore the impacts of any pharmacological intervention on downstream effects of pathway inhibition. The approach is a promising strategy in drug-discovery and could allow for reduction of off-target side effects, and more targeted treatment improving outcomes in patients.
Invention Readiness
This network-centric approach has been shown to identify small molecules capable of selectively inhibiting inflammatory pathways. This approach haS the potential to revolutionaize drug discovery. Activated NF-?B regulates signals of inflammation, proliferation, and survival through the expression of hundreds of genes and complete inhibition of all NF-?B could be lethal.
Using a large gene expression signature library, comparisons were made between the transcriptome of genetic knockdowns of proteins in the NF-?B signaling pathway and responses of the same cell types to a library of bioactive compounds. The aim was to identify compounds producing similar transcriptomes to the genetically disrupted cells. From the 717 initial hit compounds, docking studies were carried out in silico on key targets in the TNF receptor identifying three compounds of interest. Following further in vitro analysis, two of these compounds were shown to disrupt TNF-induced NF-?B signaling pathways by limiting the formation of the mature TNF receptor 1 complex.
IP Status
https://patents.google.com/patent/US20200325098A1
