Protein kinase inhibitor

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A protein kinase inhibitor is an enzyme inhibitor that blocks the action of one or more protein kinases .

properties

Protein kinases are enzymes that add a phosphoryl (PO 3 2− ) group to a protein or other organic molecule. This process is known as phosphorylation . Phosphorylation usually leads to the activation of the protein concerned, but phosphorylation can also inactivate certain proteins. The phosphate groups are usually added to the hydroxy group of the serine or threonine side chains of the proteins (by Ser / Thr protein kinases) or to tyrosine residues (by tyrosine kinases ). Dual-specific protein kinases, on the other hand, phosphorylate serine, threonine and tyrosine residues (e.g. MEK in the MAP kinase pathway ). Inhibitors for serine or threonine kinases are e.g. B. H7 (synonym (±) -1- (5-isoquinolinesulfonyl) -2-methylpiperazine dihydrochloride), H8, ML9, KN-62 and CKl-7. Therefore, protein kinase inhibitors can be classified according to the type of amino acids which they inhibit phosphorylation. There are also protein kinases that phosphorylate other amino acids, e.g. B. Histidine kinases .

Applications

In many cancers, oncogenes are constitutively , permanently and without regulation, activated through mutations . Many dysregulated oncogenes are constitutively activated protein kinases that accelerate tumor growth. Inhibiting these protein kinases has thus become an important treatment principle in cancer therapy . As with most cancer therapies, resistance can develop when used . Use of protein kinase inhibitors to treat Alzheimer's disease is being investigated. Various protein kinase inhibitors have been developed as drugs that are used depending on the cell type and genome of the particular tumor.

Individual evidence

  1. ↑ CM Norris, S. Halpain, TC Foster: Alterations in the balance of protein kinase / phosphatase activities parallel reduced synaptic strength during aging. In: Journal of neurophysiology. Volume 80, Number 3, September 1998, pp. 1567-1570, ISSN  0022-3077 . PMID 9744962 .
  2. ↑ Grahame Hardie: Protein Phosphorylation: A Practical Approach. 2nd Edition. Oxford University Press, 1999. ISBN 9780191565908 . P. 37ff.
  3. ^ OJ D'Cruz, FM Uckun: Protein kinase inhibitors against malignant lymphoma. In: Expert Opinion on Pharmacotherapy . Volume 14, Number 6, April 2013, pp. 707-721, ISSN  1744-7666 . doi : 10.1517 / 14656566.2013.780031 . PMID 23496343 . PMC 3648668 (free full text).
  4. ^ R. Krishnamurty, DJ Maly: Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors. In: ACS chemical biology. Volume 5, Number 1, January 2010, pp. 121-138, ISSN  1554-8937 . doi : 10.1021 / cb9002656 . PMID 20044834 . PMC 2879594 (free full text).
  5. ↑ V. Tell, A. Hilgeroth: Recent developments of protein kinase inhibitors as potential AD therapeutics. In: Frontiers in cellular neuroscience. Volume 7, 2013, p. 189, ISSN  1662-5102 . doi : 10.3389 / fncel.2013.00189 . PMID 24312003 . PMC 3832900 (free full text).
  6. ↑ PA Ott, S. Adams: Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. In: Immunotherapy. Volume 3, Number 2, February 2011, pp. 213-227, ISSN  1750-7448 . doi : 10.2217 / imt.10.99 . PMID 21322760 .
  7. ↑ W. Jeong, JH Doroshow, p kummar: United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. In: Current problems in cancer. Volume 37, Number 3, 2013 May-Jun, pp. 110-144, ISSN  1535-6345 . doi : 10.1016 / j.currproblcancer.2013.06.001 . PMID 23972982 . PMC 3761410 (free full text).
  8. ↑ PA Jänne, N. Gray, J. Settleman: Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. In: Nature Reviews Drug Discovery . Volume 8, Number 9, September 2009, pp. 709-723, ISSN  1474-1784 . doi : 10.1038 / nrd2871 . PMID 19629074 .