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BioAssay: AID 515830

Inhibition of human KIT autophosphorylation in human GIST882 cells by ELISA

Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, more ..
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 Tested Compounds
 Tested Compounds
All(2)
 
 
Active(2)
 
 
 Tested Substances
 Tested Substances
All(2)
 
 
Active(2)
 
 
 Related BioAssays
 Related BioAssays
AID: 515830
Data Source: ChEMBL (663684)
BioAssay Type: Confirmatory, Concentration-Response Relationship Observed
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2011-09-17
Modify Date: 2014-08-25

Data Table ( Complete ):           View Active Data    View All Data
Target
Sequence: RecName: Full=Mast/stem cell growth factor receptor Kit; Short=SCFR; AltName: Full=Piebald trait protein; Short=PBT; AltName: Full=Proto-oncogene c-Kit; AltName: Full=Tyrosine-protein kinase Kit; AltName: Full=p145 c-kit; AltName: Full=v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; AltName: CD_antigen=CD117; Flags: Precursor
Description ..   
Protein Family: Catalytic domain of the Protein Tyrosine Kinase, Kit
Comment ..   

Gene:KIT     Related Protein 3D Structures     More BioActivity Data..
BioActive Compounds: 2
Description:
Title: Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib.

Abstract: Although orphan drug applications required by the EMEA must include assessments of similarity to pre-existing products, these can be difficult to quantify. Here we illustrate a paradigm in comparing nilotinib to the prototype kinase inhibitor imatinib, and equate the degree of structural similarity to differences in properties. Nilotinib was discovered following re-engineering of imatinib, employing structural biology and medicinal chemistry strategies to optimise cellular potency and selectivity towards BCR-ABL1. Through evolving only to conserve these properties, this resulted in significant structural differences between nilotinib and imatinib, quantified by a Daylight-fingerprint-Tanimoto similarity coefficient of 0.6, with the meaning of this absolute measure being supported by an analysis of similarity distributions of similar drug-like molecules. This dissimilarity is reflected in the drugs having substantially different preclinical pharmacology and a lack of cross-intolerance in CML patients, which translates into nilotinib being an efficacious treatment for CML, with a favourable side-effect profile.
(PMID: 20817538)
Comment
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.

Categorized Comment - additional comments and annotations
From BioAssay Depositor:
Assay Type: Binding
Target Type: Target is a single protein chain
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Result Definitions
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TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1IC50*IC50 PubChem standard valueFloatμM
3BEIBinding Efficiency Index(nM)Float
2SEISurface Efficiency Index(nM)Float
4LELigand EfficiencyFloat
5LLELipophilic Ligand EfficiencyFloat
6IC50 activity commentIC50 activity commentString
7IC50 standard flagIC50 standard flagInteger
8IC50 qualifierIC50 qualifierString
9IC50 published valueIC50 published valueFloatnM
10IC50 standard valueIC50 standard valueFloatnM
11IC50 binding domainsIC50 binding domainsString

* Activity Concentration.

Data Table (Concise)
Data Table ( Complete ):     View Active Data    View All Data
Classification
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