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BioAssay: AID 1638

Summary of Chemical Antagonists IAP-family anti-apoptotic proteins

Apoptosis plays an essential role in many aspects of normal development and physiology, becoming dysregulated in myriad diseases characterized by insufficient or excessive cell death. Caspases are intracellular proteases that are suppressed by Inhibitor of Apoptosis Proteins (IAPs), a family of evolutionarily conserved anti-apoptotic proteins. Proteins released from mitochondria (SMAC and HtrA2) more ..
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 Tested Compounds
 Tested Compounds
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
 Tested Substances
 Tested Substances
All(3)
 
 
Probe(3)
 
 
Active(3)
 
 
AID: 1638
Data Source: Burnham Center for Chemical Genomics (BCCG-A168-XIAP-Summary-Assay)
BioAssay Type: Summary, Candidate Probes/Leads with Supporting Evidence
Depositor Category: NIH Molecular Libraries Probe Production Network
BioAssay Version:
Deposit Date: 2009-03-30
Modify Date: 2011-03-15

Data Table ( Complete ):           Active    All
Target
BioActive Compounds: Chemical Probe: 3    Active: 3
Depositor Specified Assays
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AIDNameTypeComment
1018Chemical Antagonists IAP-family anti-apoptotic proteinsconfirmatoryPrimary and confirmation screen using DMSO samples
1513Counter Screen using XIAP-Bir3 for Chemical Antagonists of Bir1/2 domains of IAP-family anti-apoptotic proteinsconfirmatoryCounter Screen using DMSO samples
1514Counter Screen using XIAP-Bir3 of the Chemical Antagonists of IAP-family anti-apoptotic proteins confirmation assayconfirmatoryCounter Screen using dry powders
1449Chemical Antagonists of IAP-family anti-apoptotic proteins confirmationconfirmatorySAR using dry powders
1749SAR analysis of Antagonists of IAP-family anti-apoptotic proteinsconfirmatorySAR analysis of Bir1/2 inhibitors
1750SAR analysis of Antagonists of XIAP-Bir3 domain of IAP-family anti-apoptotic proteinsconfirmatorySAR analysis of Bir3 inhibitors
485369SAR analysis of the effect of Antagonists of IAP-family anti-apoptotic proteins on rhTRAIL in MDA-MB-231 cellsotherSAR analysis of the effect of Antagonists of IAP-family anti-apoptotic proteins on rhTRAIL in MDA-MB-231 cells
485370SAR analysis of the effect of Antagonists of IAP-family anti-apoptotic proteins on rhTRAIL in HeLa cellsotherSAR analysis of the effect of Antagonists of IAP-family anti-apoptotic proteins on rhTRAIL in HeLa cells
488963SAR analysis of Antagonists of XIAP-Bir3 domain of IAP-family anti-apoptotic proteins - Set 2confirmatory
488957SAR analysis of Antagonists of IAP-family anti-apoptotic proteins - Set 2confirmatory
Description:
Data Source: Sanford-Burnham Center for Chemical Genomics (SBCCG)
Source Affiliation: Sanford-Burnham Medical Research Institute (SBMRI, San Diego, CA)
Network: NIH Molecular Libraries Probe Production Centers Network (MLPCN)
Grant Proposal Number: MH081277-01
Assay Provider: John C. Reed, Sanford-Burnham Medical Research Institute, San Diego, CA

Apoptosis plays an essential role in many aspects of normal development and physiology, becoming dysregulated in myriad diseases characterized by insufficient or excessive cell death. Caspases are intracellular proteases that are suppressed by Inhibitor of Apoptosis Proteins (IAPs), a family of evolutionarily conserved anti-apoptotic proteins. Proteins released from mitochondria (SMAC and HtrA2) can competitively displace IAPs from the Caspases, thus helping to drive apoptosis. It has been shown that only a few residues at the N-terminus of activated SMAC protein (4'mer) are sufficient to affect the release of IAPs from Caspases. Thus, it is plausible to identify chemical compounds that mimic the effect of SMAC in antagonizing IAPs by causing them to release Caspases. Non-peptidyl chemical inhibitors would have advantages over SMAC peptides, in terms of cell permeability, stability, and in vivo pharmacology. Thus, the goal of this project is to generate small-molecule chemical probe compounds that mimic the effects of SMAC peptides, inhibiting the function of IAPs.

In an earlier assay we screened libraries of small molecules for their ability to interact with the BIR1/2 substrate binding domain of XIAP(AID 1018) and BIR3(AID 1513).
This AID summarizes the assays(1018, 1449, 1513, 1514, 1749 and 1750) used to identify the probe molecules, CID25241665/SID57643995(ML101) and CID44176346/SID85164172(ML110).

Compound SID57643995, was found to be selective inhibitor of BIR1/2. The IC50 for BIR1/2(AID 1749) was about 8 times greater than that for BIR3(AID 1750), 4.0 uM vs. 32.6 uM.

Compound SID85164172 was found to be selective inhibitor of BIR1/2. The IC50 for BIR1/2(AID 1749) was about 57 times greater than that for BIR3(AID 1750), 1.8 uM vs. 102.7 uM

Compound SID85164169 was found to be selective inhibitor of BIR1/2. The IC50 for BIR1/2(AID 1749) was about 49 times greater than that for BIR3(AID 1750), 2.2 uM vs. 108.6 uM. This compound was also found to promote cell survival against a challenge by rhTrail(485369, 485370).
Protocol
Please see pertinent AIDs: 1018, 1449, 1513, 1514, 1749, 1750, 485369 and 485370
Comment
Probe molecules are defined as the positives of this assay and assigned a score of 100. Compounds, SID57643995, SID85164172 and SID85164169, were identified as probe molecules
Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
ScoreThe BioAssay activity ranking scoreInteger
1ML#ML# for the compoundString
Additional Information
Grant Number: MH081277-01

Data Table (Concise)
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