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.
authors.affiliation: Novartis Institutes for BioMedical Research, Basel, Switzerland. paul.manley@novartis.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Stiefl
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Susan
authors.initials: S
authors.lastname: Kaufman
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Markus
authors.initials: M
authors.lastname: Wartmann
authors.forename: Marion
authors.initials: M
authors.lastname: Wiesmann
authors.forename: Richard
authors.initials: R
authors.lastname: Woodman
authors.forename: Neil
authors.initials: N
authors.lastname: Gallagher
mesh_terms: D001549:Benzamides; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib