Rational design, synthesis and characterization of potent, non-peptidic Smac mimics/XIAP inhibitors as proapoptotic agents for cancer therapy.
Novel proapoptotic Smac mimics/IAPs inhibitors have been designed, synthesized and characterized. Computational models and structural studies (crystallography, NMR) have elucidated the SAR of this class of inhibitors, and have permitted further optimization of their properties. In vitro characterization (XIAP BIR3 and linker-BIR2-BIR3 binding, cytotox assays, early ADMET profiling) of the compounds has been performed, identifying one lead for further in vitro and in vivo evaluation.
Seneci
Pierfausto
P
Dipartimento di Chimica Organica e Industriale, Università degli Studi di Milano, Milan, Italy. pierfausto.seneci@unimi.it
Bianchi
Aldo
A
Battaglia
Cristina
C
Belvisi
Laura
L
Bolognesi
Martino
M
Caprini
Andrea
A
Cossu
Federica
F
Franco
Elena de
Ed
Matteo
Marilenia de
Md
Delia
Domenico
D
Drago
Carmelo
C
Khaled
Amira
A
Lecis
Daniele
D
Manzoni
Leonardo
L
Marizzoni
Moira
M
Mastrangelo
Eloise
E
Milani
Mario
M
Motto
Ilaria
I
Moroni
Elisabetta
E
Potenza
Donatella
D
Rizzo
Vincenzo
V
Servida
Federica
F
Turlizzi
Elisa
E
Varrone
Maurizio
M
Vasile
Francesca
F
Scolastico
Carlo
C
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins; D001643:Bridged Bicyclo Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D045744:Cell Line, Tumor; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000737:chemistry* / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001643:Bridged Bicyclo Compounds; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C516925:bicyclo(5.3.0)decane