Targeting IKKβ in Cancer: Challenges and Opportunities for the Therapeutic Utilisation of IKKβ Inhibitors

Area of Science:

• Molecular Biology
• Drug Discovery
• Immunology

Background:

• Nuclear factor kappa B (NF-κB) signaling deregulation is central to inflammatory diseases and cancers.
• The IKKβ protein kinase is a key mediator of canonical NF-κB signaling and a historical drug target.
• Numerous IKKβ inhibitors show preclinical promise but face clinical approval hurdles.

Purpose of the Study:

• To review the reasons behind the clinical non-success of IKKβ inhibitors.
• To discuss challenges and opportunities for IKKβ inhibitor therapeutic use.
• To explore alternative strategies for NF-κB pathway inhibition.

Main Methods:

• Literature review of IKKβ inhibitors and NF-κB pathway modulation.
• Analysis of preclinical and clinical data on IKKβ-targeted therapies.
• Evaluation of safety profiles and toxicity concerns of IKKβ inhibitors.

Main Results:

• Systemic IKKβ inhibition leads to severe on-target toxicities and safety concerns.
• Despite extensive research, no IKKβ inhibitors have gained clinical approval.
• Preclinical efficacy does not always translate to clinical success due to safety issues.

Conclusions:

• The therapeutic application of IKKβ inhibitors is limited by significant safety concerns.
• Alternative strategies to modulate the NF-κB pathway are crucial for future drug development.
• Overcoming the limitations of IKKβ inhibition may involve targeting downstream effectors or alternative pathways.