Discovery of 4-benzylamino-substituted α-carbolines as a novel class of receptor tyrosine kinase inhibitors.

Within the last decade, interest in the development of new anticancer drugs increased mainly from emerging resistance against established drugs, which were found to be limited by the multidrug resistance (MDR) phenomenon. Several anticancer targets have been investigated for the development of structurally new drugs which were thought to be unaffected by the MDR phenomenon. Receptor tyrosine kinases (RTKs) make up one interesting group of anticancer targets. The overexpression and mutation of RTKs lead to an ongoing stimulus of cell growth and cancer progression. Early approaches to selective inhibition of single RTKs were generally disappointing in clinical studies, due in part to occurring resistance. Therefore, a new strategy involves the identification of multi-kinase inhibitors to slow the development of potential resistance. Moreover, the expected side effects of the first nonselective inhibitors were less dramatic than had been expected. We have discovered novel 4-benzylamino-α-carbolines as a new class of RTK inhibitors. Docking studies suggest a binding mode to the addressed target structures of the epidermal growth factor receptor (EGFR) and to the vascular endothelial growth factor receptor 2 (VEGFR2). Selectivity profiling against a panel of kinases and antiproliferative studies have highlighted one inhibitor, active in the nanomolar range, as a highly interesting candidate for further clinical studies.