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BioAssay: AID 271015

Ratio for induction of cell death of murine BaF3 cells expressing NPM/ALK L256T mutant to wild type NPM/ALK after 16 hrs

Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inhibition studies, and molecular modeling. Mutation of the gatekeeper residue, a more ..
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 Tested Compounds
 Tested Compounds
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Unspecified(1)
 
 
 Tested Substances
 Tested Substances
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Unspecified(1)
 
 
 Related BioAssays
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AID: 271015
Data Source: ChEMBL (400216)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2010-05-25
Modify Date: 2014-05-22

Data Table ( Complete ):           All
Tested Compound:
Description:
Title: Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling.

Abstract: Anaplastic lymphoma kinase (ALK) is a valid target for anticancer therapy; however, potent ALK inhibitors suitable for clinical use are lacking. Because the majority of described kinase inhibitors bind in the ATP pocket of the kinase domain, we have characterized this pocket in ALK using site-directed mutagenesis, inhibition studies, and molecular modeling. Mutation of the gatekeeper residue, a key structural determinant influencing inhibitor binding, rendered the fusion protein, NPM/ALK, sensitive to inhibition by SKI-606 in the nanomolar range, while PD173955 inhibited the NPM/ALK mutant at micromolar concentrations. In contrast, both wild type and mutant NPM/ALK were insensitive to imatinib. Computer modeling indicated that docking solutions obtained with a homology model representing the intermediate conformation of the ALK kinase domain reflected closely experimental data. The good agreement between experimental and virtual results indicate that the ALK molecular models described here are useful tools for the rational design of ALK selective inhibitors. In addition, 4-phenylamino-quinoline compounds may have potential as templates for ALK inhibitors.
(PMID: 16970400)
Comment
Putative Target:

ChEMBL Target ID: 80036
Target Type: CELL-LINE
Cell Line: BaF3
Tissue: IL-3-dependent pro-B-cells
Pref Name: BaF3
Organism: Mus musculus
Tax ID: 10090
Confidence: Target assigned is non-molecular
Relationship Type: Non-molecular target assigned
Categorized Comment
Assay Type: Functional

Assay Data Source: Scientific Literature

BAO: Assay Format: cell-based format

Assay Cell Type: BaF3

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1Ratio activity commentRatio activity commentString
2Ratio standard flagRatio standard flagInteger
3Ratio qualifierRatio qualifierString
4Ratio published valueRatio published valueFloat
5Ratio standard valueRatio standard valueFloat

Data Table (Concise)
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