Structure-based identification of a new IAP-targeting compound that induces cancer cell death inducing NF-κB pathway

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Inhibitors of apoptosis proteins (IAPs) are crucial regulators of cell death, inflammation, and immunity.
• Overexpression of IAPs is linked to cancer development, progression, metastasis, and resistance to chemotherapy.
• Targeting IAP protein-protein interactions offers a strategy to disrupt cancer cell survival pathways.

Purpose of the Study:

• To identify novel compounds that interfere with the assembly of pro-survival macromolecular complexes regulated by IAPs.
• To evaluate the potential of identified compounds as therapeutic agents for cancer treatment.

Main Methods:

• Rational virtual screening was employed to identify potential IAP-targeting compounds.
• In vitro binding assays were performed to assess compound interaction with IAP domains (XIAP, cIAP2 BIR1).
• In vitro studies evaluated the efficacy of the lead compound (FC2) as a single agent and in combination therapies for inducing cancer cell death.

Main Results:

• FC2 was identified as a compound that binds to the BIR1 domains of XIAP and cIAP2.
• FC2 demonstrated the ability to induce cancer cell death as a monotherapy.
• FC2 exhibited enhanced potency in combination with Smac-mimetic SM83 or TNF, prolonging NF-κB pathway activation and stabilizing the XIAP-TAB1 complex.

Conclusions:

• FC2 represents a promising lead compound for a new class of IAP-antagonists.
• This molecule has potential for developing novel cancer therapeutics targeting IAP-mediated survival pathways.
• The findings support further development of FC2 for cancer treatment strategies.