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Bioorg Med Chem Lett. 2014 Apr 15;24(8):1948-51. doi: 10.1016/j.bmcl.2014.03.002. Epub 2014 Mar 12.

Discovery of 4-anilino α-carbolines as novel Brk inhibitors.

Author information

1
Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
2
ProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, Germany.
3
Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. Electronic address: andreas.hilgeroth@pharmazie.uni-halle.de.

Abstract

Dysregulation of cell signalling processes caused by an enhanced activity of protein kinases mainly contributes to cancer progression. Protein kinase inhibitors have been established as promising drugs that inhibit such overactive protein kinases in cancer cells. The formation of metastases, which makes a therapy difficult, remains a great challenge for cancer treatment. Recently, breast tumor kinase (Brk) was discovered as novel and interesting target for a cancer therapy because Brk participates in both cell dysregulation and metastasis. We discovered 4-anilino substituted α-carboline compounds as a novel class of highly active Brk inhibitors. In the current work, structure-activity relationships are discussed including docking results obtained for 4-anilino α-carbolines. A first profiling of selective kinase inhibition and a proof of concept for the antiproliferative effects is demonstrated. These results qualify the compounds as a promising class of novel antitumor agents.

KEYWORDS:

Anticancer activity; Brk inhibitor; Structure–activity relationships; α-Carbolines

PMID:
24650640
DOI:
10.1016/j.bmcl.2014.03.002
[Indexed for MEDLINE]

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