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 ..
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)
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
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
ChEMBL Assay Type: ADMET
ChEMBL Assay Data Source: Scientific Literature
ChEMBL Assay Data Source: Scientific Literature
Result Definitions
| TID | Name | Description | Histogram | Type | Unit | |
|---|---|---|---|---|---|---|
| Outcome | The BioAssay activity outcome | Outcome | ||||
| 1 | MTD activity comment | MTD activity comment | String | |||
| 2 | MTD standard flag | MTD standard flag |  | Integer | ||
| 3 | MTD qualifier | MTD qualifier | String | |||
| 4 | MTD published value | MTD published value | | Float | mg | |
| 5 | MTD standard value | MTD standard value | | Float | mg |
Data Table (Concise)
PageFrom: