title: Discovery of 4-anilino α-carbolines as novel Brk inhibitors.
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.
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Kazem Ahmed
authors.initials: KA
authors.lastname: Mahmoud
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Krug
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Tom
authors.initials: T
authors.lastname: Wersig
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Inna
authors.initials: I
authors.lastname: Slynko
authors.affiliation: ProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schächtele
authors.affiliation: ProQinase GmbH Freiburg, Breisacher Straße 117, 79106 Freiburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Totzke
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sippl
authors.affiliation: Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Str. 4, 06120 Halle, Germany. Electronic address: andreas.hilgeroth@pharmazie.uni-halle.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002243:Carbolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016503:Drug Delivery Systems; D055808:Drug Discovery; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; D002243:Carbolines; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C055571:alpha-carboline; D011505:Protein-Tyrosine Kinases; C088375:PTK6 protein, human; C023650:aniline
keywords: Anticancer activity; Brk inhibitor; Structure–activity relationships; α-Carbolines