Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer cells evade apoptosis through dysregulated inhibitor of apoptosis (IAP) proteins.
• SMAC (DIABLO) antagonizes IAPs via its AVPI motif, inhibiting cancer cell survival.
• SMAC-mimetic compounds are developed to restore apoptosis in cancer cells.

Purpose of the Study:

• To conduct preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound.
• To evaluate birinapant's efficacy in overcoming IAP-mediated apoptosis resistance in cancer cells.
• To assess birinapant's potential in combination with chemotherapies.

Main Methods:

• In vitro binding assays to assess birinapant's interaction with IAP BIR domains.
• Cell-based assays to evaluate birinapant-induced autoubiquitylation, degradation of cIAP1/cIAP2, and caspase-8 activation.
• Assessment of birinapant's effect on TNF-induced NF-κB activation.
• Evaluation of birinapant's potentiation of chemotherapeutic drug activity.
• Inhibition of tumor growth in patient-derived xenotransplant models.

Main Results:

• Birinapant binds to BIR3 domains of cIAP1, cIAP2, XIAP, and ML-IAP.
• Birinapant induces cIAP1/cIAP2 degradation, leading to RIPK1:caspase-8 complex formation, caspase-8 activation, and tumor cell death.
• Birinapant inhibits TNF-induced NF-κB activation by targeting TRAF2-associated cIAP1/cIAP2.
• Birinapant potentiates various chemotherapeutic agents and inhibits tumor growth in preclinical models at well-tolerated doses.

Conclusions:

• Birinapant effectively overcomes IAP-mediated apoptosis resistance through degradation of cIAP1/cIAP2.
• Birinapant demonstrates preclinical efficacy as a monotherapy and in combination with chemotherapeutics.
• Birinapant shows therapeutic potential, particularly with TNF-inducing therapies, supporting its clinical development.