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BioAssay: AID 515841

Toxicity in chronic CML patient assessed as maximum tolerated dose

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(1)
 
 
Unspecified(1)
 
 
 Tested Substances
 Tested Substances
All(1)
 
 
Unspecified(1)
 
 
 Related BioAssays
 Related BioAssays
AID: 515841
Data Source: ChEMBL (663695)
Depositor Category: Literature, Extracted
BioAssay Version:
Deposit Date: 2011-09-17
Modify Date: 2014-05-27

Data Table ( Complete ):           View All Data
Tested Compound:
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
Putative Target:

ChEMBL Target ID: 50587
Target Type: ORGANISM
Pref Name: Homo sapiens
Organism: Homo sapiens
Tax ID: 9606
Confidence: Target assigned is non-molecular
Relationship Type: Non-molecular target assigned
Categorized Comment
Assay Type: ADME

Assay Data Source: Scientific Literature

BAO: Assay Format: organism-based format

Result Definitions
TIDNameDescriptionHistogramTypeUnit
OutcomeThe BioAssay activity outcomeOutcome
1MTD activity commentMTD activity commentString
2MTD standard flagMTD standard flagInteger
3MTD qualifierMTD qualifierString
4MTD published valueMTD published valueFloatmg
5MTD standard valueMTD standard valueFloatmg

Data Table (Concise)
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