title: Urea derivatives of STI571 as inhibitors of Bcr-Abl and PDGFR kinases.
abstract: The constitutively active Abl kinase activity of the Bcr-Abl oncoprotein is causative for chronic myelogenous leukemia. Urea derivatives, structurally related to the therapeutic agent STI571, have been identified, which potently inhibit the tyrosine kinase activity of recombinant Abl. In particular a dimethylamino-aniline derivative (18) inhibited c-Abl transphosphorylation with an IC(50) value of 56 nM. Although this activity was not translated into cellular activity against the constitutively activated oncogenic Bcr-Abl, a number of compounds from this series potently inhibited cellular PDGFR autophosphorylation. It was also possible to differentiate between c-Abl and PDGFR kinase inhibition, with compound 22 being selective towards Abl and 23 selective for PDGFR.
authors.affiliation: Disease Area Oncology, Novartis Institutes for Biomedical Research, CH-4002 Basel, Switzerland. paul.manley@pharma.novartis.com
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Werner
authors.initials: W
authors.lastname: Breitenstein
authors.forename: Josef
authors.initials: J
authors.lastname: Brüggen
authors.forename: Sandra W
authors.initials: SW
authors.lastname: Cowan-Jacob
authors.forename: Pascal
authors.initials: P
authors.lastname: Furet
authors.forename: Jürgen
authors.initials: J
authors.lastname: Mestan
authors.forename: Thomas
authors.initials: T
authors.lastname: Meyer
mesh_terms: D000818:Animals; D001549:Benzamides; D045744:Cell Line, Tumor; D016313:Genes, abl / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000031:analogs & derivatives* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D014508:Urea; D017479:Receptors, Platelet-Derived Growth Factor