The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian a-carbonic anhydrase isoforms Seppo Parkkila a,b , Alessio Innocenti c , Heini Kallio a , Mika Hilvo a,d , Andrea Scozzafava c , Claudiu T. Supuran c, * a Institute of Medical Technology, University of Tampere and Tampere University Hospital, Tampere, Finland b School of Medicine, University of Tampere and Tampere University Hospital, Tampere, Finland c Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm. 188, Via della Lastruccia 3, I-50019 Sesto Fiorentino (Firenze), Italy d VTT Technical Research Centre of Finland, Tietotie 2, PO Box 1000, FI-02044 VTT, Espoo, Finland article info Article history: Received 27 April 2009 Revised 1 June 2009 Accepted 2 June 2009 Available online 6 June 2009 Keywords: Imatinib Nilotinib Carbonic anhydrase Isoforms I–XV Antitumor drug 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 TM /Glee- vec TM ) and nilotinib (Tasigna TM ) were investigated for their effects on the zinc enzymes carbonic anhydras- es (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 4.1 nM–20.2 lM. CA I and CA II were the most potently inhibited isoforms (K I s of 4– 32 nM), whereas CA VA and VB showed the lowest affinity for these drugs (K I s of 5.4–20.2 lM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs. Ó 2009 Elsevier Ltd. All rights reserved. The control of cellular processes, such as cell growth, division, and death, involves signal transduction, which commonly involves the transfer of the terminal phosphate moiety of adenosine triphos- phate (ATP) to tyrosine residues on substrate proteins, assisted by the protein tyrosine kinase (PTK) family of enzymes. 1–3 Protein phosphorylation and dephosphorylation play a pivotal role in intra- cellular signaling; and for regulating such signal transduction path- ways. There are 518 protein kinases and approximately 100 protein phosphatases encoded within the human genome. 1–3 A major focus of cancer research in recent years has been to identify oncogenic molecules and the signal transduction pathways in which they are involved, in order to develop specifically targeted drugs. In cancer, as well as in other proliferative diseases, unregulated cell prolifera- tion, differentiation and survival frequently results from abnormal protein phosphorylation. Receptor and non-receptor PTKs are essen- tial enzymes in cellular signaling processes that regulate cell growth, differentiation, migration and metabolism. 1–3 Aberrant catalytic activity of many PTKs, via mutation or overexpression, plays an important role in numerous pathological conditions, the most important of which is cancer. PTKs associated with platelet-derived growth factor (PDGF) receptors, Abelson (ABL) protein, KIT protein (also known as stem cell factor [SCF] receptor), protein kinase AI (PKAI), bcl-2/bcl-xL, FLT3 (fms-related tyrosine kinase/Flk2/Stk- 2)—a receptor tyrosine kinase primarily expressed on hematopoietic cells, epidermal growth factor receptor (EGFR), and ErbB-2 trans- membrane tyrosine kinases are currently being targeted by various compounds/drugs in the treatment of cancer. 1–4 The first tyrosine kinase inhibitor to be used clinically, imatinib 1 (as mesylate salt) (Glivec TM /Gleevec TM , Novartis Pharmaceuticals) blocks activity of the Bcr-Abl oncoprotein and the cell transmembrane tyro- sine kinase receptor c-Kit, and was recently approved for several indications in the treatment on chronic myeloid leukemia (CML) and gastrointestinal stromal tumors (GIST). 3–9 In both of these examples the target protein was identified by an oncogenic, activat- ing mutation. Imatinib 1 is also a potent inhibitor of PDGFR kinase and is currently being employed for the treatment of chronic myel- omonocytic leukemia and is being evaluated in glioblastoma multi- forme, based upon evidence in these diseases of activating mutations in PDGFR. 4–9 The molecular pathogenesis of CML in par- ticular, depends on formation of the Bcr-Abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr- Abl. Based on these observations, imatinib was developed as a selec- tive inhibitor of the Bcr-Abl protein tyrosine kinase. The extraordi- nary success of imatinib in CML and GIST represents a model for molecularly targeted therapy for tumors, whereas the molecular ba- sis and the detailed mechanisms of action of this drug are still not completely understood at this moment. 10 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.06.002 * Corresponding author. Tel.: +39 055 4573005; fax: +39 055 4573385. E-mail address: claudiu.supuran@unifi.it (C.T. Supuran). Bioorganic & Medicinal Chemistry Letters 19 (2009) 4102–4106 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl