Outside of nuclear receptors, transcription factors are typically considered undruggable by large or small molecules, requiring new strategies for ligand discovery. A highly attractive transcription factor target is NF-kB; aberrant canonical NF-κB signaling is implicated in diseases from autoimmune disorders to cancer. A major challenge is the need for selective inhibition of the canonical pathway without impacting the many non-canonical NF-κB functions. A complex network of protein-protein interactions (PPIs) and protein-DNA interactions regulate NF-κB function in each of the two pathways. Here we show that a synthetic replacement of a loop that mediates formation of a critical regulator of canonical NF- κB signaling, the IKK complex, acts as a selective inhibitor with &gt;10-fold increased potency over the peptide alone. This molecule powerful tool for dissection of canonical NF-κB signaling in disease models and healthy tissues, the success of the synthetic loop replacement suggests that the general strategy could be useful for discovering modulators of the many protein-protein interactions that regulate undruggable transcription factors.<br/><br/>

Targeting NF-kappaB signaling with large and small molecules

256th National Meeting (2018)

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