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Inhibition of wild type NPM/ALK autophosphorylation activity in BaF3 cells by antiphosphotyrosine immunoblotting assay

PubChem AID
271006
Primary Citation
Structural insights into the ATP binding pocket of the anaplastic lymphoma kinase by site-directed mutagenesis, inhibitor binding analysis, and homology modeling [PMID: 16970400]
Source
External ID
BioAssay Type
Confirmatory
Tested Substances
Tested Compounds
Version
Status
Live
Dates
  • Deposit:
    2010-05-25
  • Modify:
    2020-07-03
Description
This bioassay record (AID 271006) reports results from the above primary citation. Additional data from the same publication are reported in a total of 9 BioAssay records in PubChem.

1 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.

2 Comment

Journal: J Med Chem

Year: 2006

Volume: 49

Issue: 19

First Page: 5759

Last Page: 5768

DOI: 10.1021/jm060380k

Target ChEMBL ID: CHEMBL2111387

ChEMBL Target Name: NPM/ALK (Nucleophosmin/ALK tyrosine kinase receptor)

ChEMBL Target Type: CHIMERIC PROTEIN - Target is a fusion of two different proteins, either a synthetic construct or naturally occurring fusion protein

Relationship Type: D - Direct protein target assigned

Confidence: Direct protein complex subunits assigned

3 Result Definitions

4 Data Table

5 Target

2 of 2
Protein Target
Encoding Gene
NCBI GeneID

8 Identity

8.1 BioAssay Name

Inhibition of wild type NPM/ALK autophosphorylation activity in BaF3 cells by antiphosphotyrosine immunoblotting assay

8.2 Source

8.3 External ID

8.4 Project Category

Literature, Extracted

8.5 BioAssay Type

Confirmatory

8.6 Deposit Date

2010-05-25

8.7 Modify Date

Version 1.1
Version 2.1
Version 2.2
Version 2.3
Version 2.4
Version 3.1
Version 3.2
Version 4.1
Version 4.2
Version 5.1
Version 5.2
Version 6.1
Version 6.2
Version 6.3
Version 6.4
Version 6.5
Version 6.6
Version 6.7
Version 6.8
Version 7.1
Version 7.2
2020-07-03 (currently shown)

8.8 Status

Live

9 Same-Publication BioAssays

10 BioAssay Annotations

Assay Format
Cell-based
Assay Type
Binding
Assay Cell Type
Assay Organism

11 Information Sources

  1. PubChem
  2. ChEMBL
    LICENSE
    Access to the web interface of ChEMBL is made under the EBI's Terms of Use (http://www.ebi.ac.uk/Information/termsofuse.html). The ChEMBL data is made available on a Creative Commons Attribution-Share Alike 3.0 Unported License (http://creativecommons.org/licenses/by-sa/3.0/).
    http://www.ebi.ac.uk/Information/termsofuse.html
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