title: Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2.
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.
authors.affiliation: Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, I-20133 Milano, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Cossu
authors.forename: Eloise
authors.initials: E
authors.lastname: Mastrangelo
authors.forename: Mario
authors.initials: M
authors.lastname: Milani
authors.forename: Graziella
authors.initials: G
authors.lastname: Sorrentino
authors.forename: Daniele
authors.initials: D
authors.lastname: Lecis
authors.forename: Domenico
authors.initials: D
authors.lastname: Delia
authors.forename: Leonardo
authors.initials: L
authors.lastname: Manzoni
authors.forename: Pierfausto
authors.initials: P
authors.lastname: Seneci
authors.forename: Carlo
authors.initials: C
authors.lastname: Scolastico
authors.forename: Martino
authors.initials: M
authors.lastname: Bolognesi
mesh_terms: D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins; D001381:Azepines / Q000737:chemistry* / Q000494:pharmacology; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D040761:Biomimetic Materials / Q000737:chemistry* / Q000494:pharmacology; D003461:Crystallography; D015195:Drug Design; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry; D024101:Mitochondrial Proteins / Q000737:chemistry; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001381:Azepines; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D011759:Pyrrolidines; D051636:X-Linked Inhibitor of Apoptosis Protein; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases