Abstract
Nuclear factor kappa B (NF-κB) signaling is implicated in all major human chronic diseases, with its role in transcription of hundreds of gene well established in the literature. This has propelled research into targeting the NF-κB pathways for modulating expression of those genes and the diseases mediated by them. In-spite of the critical, but often promiscuous role played by this pathway and the inhibition causing adverse drug reaction, currently many biologics, macromolecules, and small molecules that modulate this pathway are in the market or in clinical trials. Furthermore, many marketed drugs that were later found to also have NF-κB targeting activity were repurposed for new therapeutic interventions. Despite the rising importance of biologics in drug discovery, small molecules got around 76% of US-FDA (Food and Drug Administration-US) approval in the last decade. This encouraged us to review information regarding clinically relevant small molecule inhibitors of the NF-κB pathway from cell surface receptor stimulation to nuclear signaling. We have also highlighted the underexplored targets in this pathway that have potential to succeed in clinic.
Highlights
Nuclear factor kappa B (NF-κB) signaling has been well studied for more than three decades from the first report by Sen et al [1] in 1986
Apart from evaluating the successes and failures of these small molecule NF-κB inhibitors during clinical trials, we reviewed drugs that have been re-purposed after being shown to have NF-κB activity
Active CA-4948 (AU-4948) that was out-licensed to Curis by Aurigene, is currently in phase 1 for acute myeloid leukemia (AML), Myelodysplastic syndromes and non-Hodgkin lymphoma (NHL) [87]
Summary
Nuclear factor kappa B (NF-κB) signaling has been well studied for more than three decades from the first report by Sen et al [1] in 1986. TLR4 antagonist, JKB-121, a small molecule inhibitor developed by TaiwanJ Pharmaceuticals for the non-alcoholic steatohepatitis (NASH) indication, is in jeopardy after it failed to demonstrate efficacy in a phase 2 placebo-controlled trial due to surprising positive response in the placebo arm [41]. Denosumab is a human recombinant monoclonal antibody against RANKL that has achieved orphan drug status [44] for bone cancer and malignant hypercalcemia and is currently marketed for these disease conditions along with other bone disorders, bone metastases, corticosteroid-induced osteoporosis, and male osteoporosis [45,46] It is currently in phase 3 for breast cancer and non-small cell lung cancer (NSCLC) but there are concerns of increased risk of spontaneous multiple vertebral fractures upon denosumab discontinuation that has to be managed by bisphosphonate [47].
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