Document Detail


Expedient synthesis of highly potent antagonists of inhibitor of apoptosis proteins (IAPs) with unique selectivity for ML-IAP.
MedLine Citation:
PMID:  23323685     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
A series of novel, potent antagonists of the inhibitor of apoptosis proteins (IAPs) were synthesized in a highly convergent and rapid fashion (≤6 steps) using the Ugi four-component reaction as the key step, thus enabling rapid optimization of binding potency. These IAP antagonists compete with caspases 3, 7, and 9 for inhibition by X chromosome-linked IAP (XIAP) and bind strongly (nanomolar binding constants) to several crucial members of the IAP family of cancer pro-survival proteins to promote apoptosis, with a particularly unique selectivity for melanoma IAP (ML-IAP). Experiments in cell culture revealed powerful cancer cell growth inhibitory activity in multiple (breast, ovarian, and prostate) cell lines with single agent toxicity at low nanomolar levels against SKOV-3 human ovarian carcinoma cells. Administration of the compounds to human foreskin fibroblast cells revealed no general toxicity to normal cells. Furthermore, computational modeling was performed, revealing key contacts between the IAP proteins and antagonists, suggesting a structural basis for the observed potency.
Authors:
Mitchell Vamos; Kate Welsh; Darren Finlay; Pooi San Lee; Peter D Mace; Scott J Snipas; Monica L Gonzalez; Santhi Reddy Ganji; Robert J Ardecky; Stefan J Riedl; Guy S Salvesen; Kristiina Vuori; John C Reed; Nicholas D P Cosford
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-02-05
Journal Detail:
Title:  ACS chemical biology     Volume:  8     ISSN:  1554-8937     ISO Abbreviation:  ACS Chem. Biol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-19     Completed Date:  2013-10-17     Revised Date:  2014-04-22    
Medline Journal Info:
Nlm Unique ID:  101282906     Medline TA:  ACS Chem Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  725-32     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Caspase Inhibitors / pharmacology
Drug Design
Fluorescence Polarization
Inhibitor of Apoptosis Proteins / antagonists & inhibitors*,  metabolism
Melanoma / metabolism*
Models, Molecular
Grant Support
ID/Acronym/Agency:
CA081534/CA/NCI NIH HHS; P01 CA081534/CA/NCI NIH HHS; P20 CA081534/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS; R03 MH081277/MH/NIMH NIH HHS; R03 MH081277/MH/NIMH NIH HHS; U01 CA113318/CA/NCI NIH HHS; U54 HG00503/HG/NHGRI NIH HHS; U54 HG005033/HG/NHGRI NIH HHS
Chemical
Reg. No./Substance:
0/Caspase Inhibitors; 0/Inhibitor of Apoptosis Proteins
Comments/Corrections

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