title: The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian alpha-carbonic anhydrase isoforms.
abstract: The protein tyrosine kinases (PTKs) are essential enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. Their inhibition was recently shown to constitute a new modality for treating cancers. Two clinically used PTK inhibitors (PTKIs), imatinib (Glivec/Gleevec) and nilotinib (Tasigna) were investigated for their effects on the zinc enzymes carbonic anhydrases (CAs, EC 4.2.1.1). The two PTKIs inhibited all 13 catalytically active mammalian isoforms CA I-XV with K(I)s in the range of 4.1nM-20.2microM. CA I and CA II were the most potently inhibited isoforms (K(I)s of 4-32nM), whereas CA VA and VB showed the lowest affinity for these drugs (K(I)s of 5.4-20.2microM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs.
authors.affiliation: Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland.
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
authors.forename: Alessio
authors.initials: A
authors.lastname: Innocenti
authors.forename: Heini
authors.initials: H
authors.lastname: Kallio
authors.forename: Mika
authors.initials: M
authors.lastname: Hilvo
authors.forename: Andrea
authors.initials: A
authors.lastname: Scozzafava
authors.forename: Claudiu T
authors.initials: CT
authors.lastname: Supuran
mesh_terms: D000818:Animals; D001549:Benzamides; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000737:chemistry*; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D006863:Hydrogen-Ion Concentration; D000068877:Imatinib Mesylate; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis / Q000494:pharmacology*; D020033:Protein Isoforms; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D015032:Zinc / Q000737:chemistry
chemical_list: D001549:Benzamides; D002257:Carbonic Anhydrase Inhibitors; D010879:Piperazines; D020033:Protein Isoforms; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D002256:Carbonic Anhydrases; C498826:nilotinib; D015032:Zinc