Inhibition of autophosphorylation of BCR-ABL1 expressed in Ba/F cells
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 ..
BioActive Compounds: 2
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.
Compounds with activity <= 50uM or explicitly reported as active by ChEMBL are flagged as active in this PubChem assay presentation.
ChEMBL Target ID: 104811
Target Type: CHIMERIC PROTEIN
Pref Name: Bcr/Abl fusion protein
Synonyms: Abelson murine leukemia viral oncogene homolog 1;Abelson tyrosine-protein kinase 1;p150;Proto-oncogene c-Abl;Tyrosine-protein kinase ABL1;Breakpoint cluster region protein;Renal carcinoma antigen NY-REN-26;
Gene Name: ABL ;ABL1;JTK7;BCR;BCR1 ;D22S11;
Protein Accession: P00519;P11274;
Protein GI: 85681908;143811366;
Organism: Homo sapiens
Tax ID: 9606
Target Classification 1: cytosolic other
Target Classification 2: enzyme kinase protein kinase atypical bcr
Target Classification 3: enzyme kinase protein kinase tk abl
Confidence: Homologous protein complex subunits assigned
Relationship Type: Homologous protein target assigned
Assay Type: Binding
Assay Data Source: Scientific Literature
Assay Test Type: In vitro
BAO: Assay Format: cell-based format
* Activity Concentration.
Data Table (Concise)