Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2

Federica Cossu; Eloise Mastrangelo; Mario Milani; Graziella Sorrentino; Daniele Lecis; Domenico Delia; Leonardo Manzoni; Pierfausto Seneci; Carlo Scolastico; Martino Bolognesi

doi:10.1016/j.bbrc.2008.10.139

Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2

Biochem Biophys Res Commun. 2009 Jan 9;378(2):162-7. doi: 10.1016/j.bbrc.2008.10.139. Epub 2008 Nov 4.

Authors

Federica Cossu¹, Eloise Mastrangelo, Mario Milani, Graziella Sorrentino, Daniele Lecis, Domenico Delia, Leonardo Manzoni, Pierfausto Seneci, Carlo Scolastico, Martino Bolognesi

Affiliation

¹ Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, I-20133 Milano, Italy.

PMID: 18992220
DOI: 10.1016/j.bbrc.2008.10.139

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Apoptosis Regulatory Proteins
Azepines / chemistry*
Azepines / pharmacology
Baculoviral IAP Repeat-Containing 3 Protein
Biomimetic Materials / chemistry*
Biomimetic Materials / pharmacology
Crystallography
Drug Design
Humans
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*
Inhibitor of Apoptosis Proteins / chemistry
Intracellular Signaling Peptides and Proteins / chemistry
Mitochondrial Proteins / chemistry
Molecular Sequence Data
Protein Structure, Tertiary
Pyrrolidines / chemistry*
Pyrrolidines / pharmacology
Ubiquitin-Protein Ligases
X-Linked Inhibitor of Apoptosis Protein / antagonists & inhibitors*
X-Linked Inhibitor of Apoptosis Protein / chemistry

Substances

Antineoplastic Agents
Apoptosis Regulatory Proteins
Azepines
DIABLO protein, human
Inhibitor of Apoptosis Proteins
Intracellular Signaling Peptides and Proteins
Mitochondrial Proteins
Pyrrolidines
X-Linked Inhibitor of Apoptosis Protein
BIRC3 protein, human
Baculoviral IAP Repeat-Containing 3 Protein
Ubiquitin-Protein Ligases