Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization.
Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.
Dipartimento di Oncologia Sperimentale e Medicina Molecolare, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Amadeo 42, Milan, Italy.
Daniele
D
Lecis
Eloise
E
Mastrangelo
Laura
L
Belvisi
Martino
M
Bolognesi
Monica
M
Civera
Federica
F
Cossu
Michelandrea
M
De Cesare
Domenico
D
Delia
Carmelo
C
Drago
Giacomo
G
Manenti
Leonardo
L
Manzoni
Mario
M
Milani
Elisabetta
E
Moroni
Paola
P
Perego
Donatella
D
Potenza
Vincenzo
V
Rizzo
Cinzia
C
Scavullo
Carlo
C
Scolastico
Federica
F
Servida
Francesca
F
Vasile
Pierfausto
P
Seneci
D000818:Animals; D001665:Binding Sites; D040761:Biomimetic Materials / Q000737:chemistry* / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018360:Crystallography, X-Ray; D019281:Dimerization; D005260:Female; D018922:HL-60 Cells; D006207:Half-Life; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D056004:Molecular Dynamics Simulation; D019906:Nuclear Magnetic Resonance, Biomolecular; D009842:Oligopeptides / Q000737:chemistry*; D010051:Ovarian Neoplasms / Q000188:drug therapy; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
D051034:Inhibitor of Apoptosis Proteins; D009842:Oligopeptides; C532637:SMAC peptide