Discovery of 4-anilino alpha-carbolines as novel Brk inhibitors

作者：Mahmoud Kazem Ahmed; Krug Martin; Wersig Tom; Slynko Inna; Schaechtele Christoph; Totzke Frank; Sippl Wolfgang; Hilgeroth Andreas^*

来源：Bioorganic & Medicinal Chemistry Letters, 2014, 24(8): 1948-1951.

DOI：10.1016/j.bmcl.2014.03.002

• alpha-Carbolines
• Brk inhibitor
• Structure-activity relationships
• Anticancer activity

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 a-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 alpha-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.

• 出版日期2014-4-15