Inhibition of autophosphorylation of DDR1 expressed in HEK293 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 ..
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: 100917
Target Type: SINGLE PROTEIN
Pref Name: Epithelial discoidin domain-containing receptor 1
Synonyms: CD167 antigen-like family member A;CD_antigen=CD167a;Cell adhesion kinase;Discoidin receptor tyrosine kinase;Epithelial discoidin domain receptor 1;Epithelial discoidin domain-containing receptor 1;HGK2;Mammary carcinoma kinase 10;MCK-10;Protein-tyrosine kinase 3A;Protein-tyrosine kinase RTK-6;TRK E;Tyrosine kinase DDR;Tyrosine-protein kinase CAK;
Gene Name: CAK ;DDR1;EDDR1;NEP;NTRK4;PTK3A;RTK6;TRKE;
Protein Accession: Q08345;
Protein GI: 729008;
Organism: Homo sapiens
Tax ID: 9606
Target Classification: enzyme kinase protein kinase tk ddr
Confidence: Homologous single protein target assigned
Relationship Type: Homologous protein target assigned
Categorized Comment - additional comments and annotations
Assay Type: Binding
Assay Data Source: Scientific Literature
BAO: Assay Format: cell-based format
Assay Cell Type: HEK293
* Activity Concentration.
Data Table (Concise)