The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian α-carbonic anhydrase isoforms

Seppo Parkkila, Alessio Innocenti, Heini Kallio, Mika Hilvo, Andrea Scozzafava, Claudiu T. Supuran (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

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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 KIs in the range of 4.1 nM–20.2 μM. CA I and CA II were the most potently inhibited isoforms (KIs of 4–32 nM), whereas CA VA and VB showed the lowest affinity for these drugs (KIs of 5.4–20.2 μM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs.
Original languageEnglish
Pages (from-to)4102-4106
Number of pages5
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number15
DOIs
Publication statusPublished - 2009
MoE publication typeA1 Journal article-refereed

Fingerprint

Carbonic Anhydrases
Protein Kinase Inhibitors
Protein-Tyrosine Kinases
Protein Isoforms
Cell signaling
Enzyme inhibition
Cell growth
Enzymes
Metabolism
Zinc
Cell Differentiation
Neoplasms
Cells
Pharmaceutical Preparations
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Imatinib Mesylate

Keywords

  • Imatinib
  • Nilotinib
  • Carbonic anhydrase
  • Isoforms I-XV
  • Antitumor drug

Cite this

Parkkila, Seppo ; Innocenti, Alessio ; Kallio, Heini ; Hilvo, Mika ; Scozzafava, Andrea ; Supuran, Claudiu T. / The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian α-carbonic anhydrase isoforms. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 15. pp. 4102-4106.
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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 KIs in the range of 4.1 nM–20.2 μM. CA I and CA II were the most potently inhibited isoforms (KIs of 4–32 nM), whereas CA VA and VB showed the lowest affinity for these drugs (KIs of 5.4–20.2 μM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs.",
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The protein tyrosine kinase inhibitors imatinib and nilotinib strongly inhibit several mammalian α-carbonic anhydrase isoforms. / Parkkila, Seppo; Innocenti, Alessio; Kallio, Heini; Hilvo, Mika; Scozzafava, Andrea; Supuran, Claudiu T. (Corresponding Author).

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 15, 2009, p. 4102-4106.

Research output: Contribution to journalArticleScientificpeer-review

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AU - Parkkila, Seppo

AU - Innocenti, Alessio

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AU - Scozzafava, Andrea

AU - Supuran, Claudiu T.

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AB - 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 KIs in the range of 4.1 nM–20.2 μM. CA I and CA II were the most potently inhibited isoforms (KIs of 4–32 nM), whereas CA VA and VB showed the lowest affinity for these drugs (KIs of 5.4–20.2 μM). In cancer cells, these inhibitors may interact with CAs in addition to the targets for which they were designed, the PTKs.

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