Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib.

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Manley PW, Stiefl N, Cowan-Jacob SW, Kaufman S, Mestan J, Wartmann M, Wiesmann M, Woodman R, Gallagher N

Structural resemblances and comparisons of the relative pharmacological properties of imatinib and nilotinib.

Bioorg Med Chem. 2010 Oct 1;18(19):6977-86. doi: 10.1016/j.bmc.2010.08.026. Epub 2010 Aug 14.

PubMed ID
20817538 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ImatinibEpithelial discoidin domain-containing receptor 1IC 50 (nM)43N/AN/ADetails
ImatinibMacrophage colony-stimulating factor 1 receptorIC 50 (nM)291N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor alphaIC 50 (nM)72N/AN/ADetails
ImatinibPlatelet-derived growth factor receptor betaIC 50 (nM)72N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1IC 50 (nM)473N/AN/ADetails
ImatinibTyrosine-protein kinase ABL1IC 50 (nM)221N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1IC 50 (nM)42N/AN/ADetails
NilotinibTyrosine-protein kinase ABL1IC 50 (nM)20N/AN/ADetails