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Updated: Jun 28, 2026
Protein WISDOM: A Workbench for In silico De novo Design of BioMolecules
Published on: July 25, 2013
Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2
Federica Cossu1, Eloise Mastrangelo, Mario Milani
1Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
Abstract:
Inhibitor of apoptosis proteins (IAPs) such as XIAP, cIAP1, and cIAP2 are upregulated in many cancer cells. Several compounds targeting IAPs and inducing cell death in cancer cells have been developed. Some of these are synthesized mimicking the N-terminal tetrapeptide sequence of Smac/DIABLO, the natural endogenous IAPs inhibitor. Starting from such conceptual design, we generated a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics. Here we report the crystal structure of the BIR3 domain from XIAP in complex with Smac037, a compound designed according to structural principles emerging from our previously analyzed XIAP BIR3/Smac-mimetic complexes. In parallel, we present an in silico docking analysis of three Smac-mimetics to the BIR3 domain of cIAP1, providing general considerations for the development of high affinity lead compounds targeting three members of the IAP family.
Insights
New Smac-mimetic compounds targeting inhibitor of apoptosis proteins (IAPs) show promise for cancer therapy. Researchers determined the crystal structure of XIAP
Area of Science:
- Biochemistry
- Structural Biology
- Medicinal Chemistry
Background:
- Inhibitor of apoptosis proteins (IAPs) are frequently overexpressed in cancers, promoting tumor cell survival.
- Smac/DIABLO is a natural inhibitor of IAPs, and its sequence inspires the design of therapeutic agents.
- Targeting IAPs offers a promising strategy for cancer treatment.
Purpose of the Study:
- To design and synthesize novel Smac-mimetics based on the Smac/DIABLO tetrapeptide sequence.
- To elucidate the structural basis of interaction between Smac-mimetics and IAP BIR3 domains.
- To provide insights for developing high-affinity compounds targeting XIAP, cIAP1, and cIAP2.
Main Methods:
- Generation of a library of 4-substituted azabicyclo[5.3.0]alkane Smac-mimetics.
- X-ray crystallography to determine the structure of XIAP BIR3 domain complexed with Smac037.
- In silico molecular docking analysis of Smac-mimetics with the cIAP1 BIR3 domain.
Main Results:
- The crystal structure of XIAP BIR3 in complex with Smac037 was determined.
- Smac037 was designed based on structural principles from prior XIAP BIR3/Smac-mimetic complexes.
- In silico analysis provided insights into the binding of Smac-mimetics to cIAP1 BIR3.
Conclusions:
- The study presents a novel Smac-mimetic, Smac037, with potential as an anti-cancer therapeutic.
- Structural and computational analyses offer a foundation for optimizing Smac-mimetics for enhanced affinity and specificity.
- These findings contribute to the development of targeted therapies against IAP-overexpressing cancers.
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