Src-Inhibitor

Ein Src-Inhibitor ist ein Proteinkinaseinhibitor, der die Tyrosinkinase Src hemmt.[1]

Eigenschaften

Die Tyrosinkinase Src (von engl. Sarcoma) ist ein Onkogen, das an der malignen Transformation von Zellen beteiligt ist.[2] Eine Hemmung dieser Proteinkinase ist damit eine Behandlungsform in der Krebstherapie.[3] Wie bei den meisten Krebstherapien können bei Verwendung Resistenzen entstehen,[4] weshalb Kombinationstherapien zur Vermeidung einer Resistenzbildung durch Erhöhung des Selektionsdrucks untersucht werden.[5] Proteinkinaseinhibitoren werden je nach Zelltyp und Genom des jeweiligen Tumors verwendet.[6][7][8]

Beispiele

Ponatinib

KX2-391 ist oral bioverfügbar und besitzt eine GI₅₀ von 9 bis 60 nM in Krebs-Zelllinien.[9]
Bosutinib
Ponatinib
Saracatinib[10]
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.