TY - JOUR
T1 - Designing Smac-mimetics as antagonists of XIAP, cIAP1, and cIAP2
AU - Cossu, Federica
AU - Mastrangelo, Eloise
AU - Milani, Mario
AU - Sorrentino, Graziella
AU - Lecis, Daniele
AU - Delia, Domenico
AU - Manzoni, Leonardo
AU - Seneci, Pierfausto
AU - Scolastico, Carlo
AU - Bolognesi, Martino
PY - 2009/1/9
Y1 - 2009/1/9
N2 - 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.
AB - 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.
KW - cIAP
KW - Inhibition of apoptosis
KW - Oncology
KW - Peptidomimetics
KW - SMAC/DIABLO
KW - XIAP
UR - http://www.scopus.com/inward/record.url?scp=57049144228&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=57049144228&partnerID=8YFLogxK
U2 - 10.1016/j.bbrc.2008.10.139
DO - 10.1016/j.bbrc.2008.10.139
M3 - Article
C2 - 18992220
AN - SCOPUS:57049144228
VL - 378
SP - 162
EP - 167
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
SN - 0006-291X
IS - 2
ER -