Src-Inhibitor

Ein Src-Inhibitor ist ein Proteinkinaseinhibitor, der die Tyrosinkinase Src hemmt.

Eigenschaften

Die Tyrosinkinase Src (von engl. Sarcoma) ist ein Onkogen, das an der malignen Transformation von Zellen beteiligt ist. Eine Hemmung dieser Proteinkinase ist damit eine Behandlungsform in der Krebstherapie. Wie bei den meisten Krebstherapien können bei Verwendung Resistenzen entstehen, weshalb Kombinationstherapien zur Vermeidung einer Resistenzbildung durch Erhöhung des Selektionsdrucks untersucht werden. Proteinkinaseinhibitoren werden je nach Zelltyp und Genom des jeweiligen Tumors verwendet.

Beispiele

KX2-391 ist oral bioverfügbar und besitzt eine GI₅₀ von 9 bis 60 nM in Krebs-Zelllinien.
Bosutinib
Ponatinib
Saracatinib
PP1 und PP2 sind Hemmer von den Tyrosinkinasen Lck und FynT.
Quercetin
Dasatinib

Literatur

A. Aleshin, R. S. Finn: SRC: a century of science brought to the clinic. In: Neoplasia. Band 12, Nummer 8, August 2010, S. 599–607, ISSN 1476-5586. PMID 20689754. PMC 2915404 (freier Volltext).
N. A. Chatzizacharias, G. P. Kouraklis, C. T. Giaginis, S. E. Theocharis: Clinical significance of Src expression and activity in human neoplasia. In: Histology and histopathology. Band 27, Nummer 6, Juni 2012, S. 677–692, ISSN 1699-5848. PMID 22473690.

Einzelnachweise

↑ H. Creedon, V. G. Brunton: Src kinase inhibitors: promising cancer therapeutics? In: Critical reviews in oncogenesis. Band 17, Nummer 2, 2012, S. 145–159, ISSN 0893-9675. PMID 22471705.
↑ B. Elsberger, B. Stewart, O. Tatarov, J. Edwards: Is Src a viable target for treating solid tumours? In: Current Cancer Drug Targets. Band 10, Nummer 7, November 2010, S. 683–694, ISSN 1873-5576. PMID 20578988.
↑ L. N. Puls, M. Eadens, W. Messersmith: Current status of SRC inhibitors in solid tumor malignancies. In: The Oncologist. Band 16, Nummer 5, 2011, S. 566–578, ISSN 1549-490X. doi:10.1634/theoncologist.2010-0408. PMID 21521831. PMC 3228195 (freier Volltext).
↑ R. Krishnamurty, D. J. Maly: Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors. In: ACS Chemical Biology. Band 5, Nummer 1, Januar 2010, S. 121–138, ISSN 1554-8937. doi:10.1021/cb9002656. PMID 20044834. PMC 2879594 (freier Volltext).
↑ S. Hiscox, P. Barrett-Lee, A. C. Borley, R. I. Nicholson: Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss. In: European Journal of Cancer (Oxford, England : 1990). Band 46, Nummer 12, August 2010, S. 2187–2195, ISSN 1879-0852. doi:10.1016/j.ejca.2010.04.012. PMID 20471823.
↑ P. A. Jänne, N. Gray, J. Settleman: Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. In: Nature Reviews Drug Discovery. Band 8, Nummer 9, September 2009, S. 709–723, ISSN 1474-1784. doi:10.1038/nrd2871. PMID 19629074.
↑ P. A. Ott, S. Adams: Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. In: Immunotherapy. Band 3, Nummer 2, Februar 2011, S. 213–227, ISSN 1750-7448. doi:10.2217/imt.10.99. PMID 21322760.
↑ W. Jeong, J. H. Doroshow, S. Kummar: United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. In: Current Problems in Cancer. Band 37, Nummer 3, 2013 May-Jun, S. 110–144, ISSN 1535-6345. doi:10.1016/j.currproblcancer.2013.06.001. PMID 23972982. PMC 3761410 (freier Volltext).
↑ Antonarakis ES, Heath EI, Posadas EM, Yu EY et al.: A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. In: Cancer Chemother Pharmacol. 71. Jahrgang, Nr. 4, April 2013, S. 883–892, doi:10.1007/s00280-013-2079-z.
↑ H. J. Nam, S. A. Im, D. Y. Oh, P. Elvin, H. P. Kim, Y. K. Yoon, A. Min, S. H. Song, S. W. Han, T. Y. Kim, Y. J. Bang: Antitumor activity of saracatinib (AZD0530), a c-Src/Abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer. In: Molecular Cancer Therapeutics. Band 12, Nummer 1, Januar 2013, S. 16–26, ISSN 1538-8514. doi:10.1158/1535-7163.MCT-12-0109. PMID 23144237.

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[1] H. Creedon, V. G. Brunton: Src kinase inhibitors: promising cancer therapeutics? In: Critical reviews in oncogenesis. Band 17, Nummer 2, 2012, S. 145–159, ISSN 0893-9675. PMID 22471705.

[2] B. Elsberger, B. Stewart, O. Tatarov, J. Edwards: Is Src a viable target for treating solid tumours? In: Current Cancer Drug Targets. Band 10, Nummer 7, November 2010, S. 683–694, ISSN 1873-5576. PMID 20578988.

[3] L. N. Puls, M. Eadens, W. Messersmith: Current status of SRC inhibitors in solid tumor malignancies. In: The Oncologist. Band 16, Nummer 5, 2011, S. 566–578, ISSN 1549-490X. doi:10.1634/theoncologist.2010-0408. PMID 21521831. PMC 3228195 (freier Volltext).

[4] R. Krishnamurty, D. J. Maly: Biochemical mechanisms of resistance to small-molecule protein kinase inhibitors. In: ACS Chemical Biology. Band 5, Nummer 1, Januar 2010, S. 121–138, ISSN 1554-8937. doi:10.1021/cb9002656. PMID 20044834. PMC 2879594 (freier Volltext).

[5] S. Hiscox, P. Barrett-Lee, A. C. Borley, R. I. Nicholson: Combining Src inhibitors and aromatase inhibitors: a novel strategy for overcoming endocrine resistance and bone loss. In: European Journal of Cancer (Oxford, England : 1990). Band 46, Nummer 12, August 2010, S. 2187–2195, ISSN 1879-0852. doi:10.1016/j.ejca.2010.04.012. PMID 20471823.

[6] P. A. Jänne, N. Gray, J. Settleman: Factors underlying sensitivity of cancers to small-molecule kinase inhibitors. In: Nature Reviews Drug Discovery. Band 8, Nummer 9, September 2009, S. 709–723, ISSN 1474-1784. doi:10.1038/nrd2871. PMID 19629074.

[7] P. A. Ott, S. Adams: Small-molecule protein kinase inhibitors and their effects on the immune system: implications for cancer treatment. In: Immunotherapy. Band 3, Nummer 2, Februar 2011, S. 213–227, ISSN 1750-7448. doi:10.2217/imt.10.99. PMID 21322760.

[8] W. Jeong, J. H. Doroshow, S. Kummar: United States Food and Drug Administration approved oral kinase inhibitors for the treatment of malignancies. In: Current Problems in Cancer. Band 37, Nummer 3, 2013 May-Jun, S. 110–144, ISSN 1535-6345. doi:10.1016/j.currproblcancer.2013.06.001. PMID 23972982. PMC 3761410 (freier Volltext).

[9] Antonarakis ES, Heath EI, Posadas EM, Yu EY et al.: A phase 2 study of KX2-391, an oral inhibitor of Src kinase and tubulin polymerization, in men with bone-metastatic castration-resistant prostate cancer. In: Cancer Chemother Pharmacol. 71. Jahrgang, Nr. 4, April 2013, S. 883–892, doi:10.1007/s00280-013-2079-z.

[10] H. J. Nam, S. A. Im, D. Y. Oh, P. Elvin, H. P. Kim, Y. K. Yoon, A. Min, S. H. Song, S. W. Han, T. Y. Kim, Y. J. Bang: Antitumor activity of saracatinib (AZD0530), a c-Src/Abl kinase inhibitor, alone or in combination with chemotherapeutic agents in gastric cancer. In: Molecular Cancer Therapeutics. Band 12, Nummer 1, Januar 2013, S. 16–26, ISSN 1538-8514. doi:10.1158/1535-7163.MCT-12-0109. PMID 23144237.