Design of small molecules targeting transcriptional activation by NF-κB: overview of recent advances

Area of Science:

• Molecular Biology
• Immunology
• Oncology

Background:

• Nuclear factor-kappa B (NF-κB) is a transcription factor crucial for immune responses and inflammation.
• NF-κB promotes tumor cell survival by activating antiapoptotic factors, contributing to cancer progression.
• Targeting NF-κB activation or transcription is a significant area of drug development for inflammation and cancer.

Purpose of the Study:

• To review current NF-κB signaling pathways.
• To provide an overview of three classes of NF-κB inhibitors.
• To discuss recent advancements in developing targeted NF-κB therapies.

Main Methods:

• Review of literature on NF-κB signaling pathways and inhibitors.
• Categorization of inhibitors based on their mechanism of action.
• Discussion of nuclear receptor ligands and their role in modulating NF-κB activity.

Main Results:

• Inhibitors targeting IκB kinase-β (IKK2) are effective in blocking inflammatory signaling.
• Agents that prevent NF-κB DNA binding offer a direct approach to inhibit transcription.
• Nuclear receptor ligands, like glucocorticoid receptor and PPARs, interfere with NF-κB transcription via ligand-dependent transrepression.

Conclusions:

• NF-κB inhibitors have demonstrated significant efficacy in preclinical models of inflammation and cancer.
• Development of selective ligands for nuclear receptors shows potential for targeted therapy with reduced side effects.
• Several NF-κB inhibitors are progressing into clinical trials, indicating their therapeutic potential.