Novel Functionalized Pyrrolopyridines to Target Brk

Background: Increasing resistance against protein kinase inhibitors used in cancer therapies enforces the search for novel target structures to be addressed with favourable small-molecule inhibitors. One of these novel target structures is the tyrosine kinase Brk that is known to play a prominent role in breast cancer progression. Moreover, Brk overexpression in various kinds of cancer is associated with poor outcomes, making Brk an interesting target structure for potential treatment. So far, no class of promising Brk inhibitors has been identified. Methods: We synthesized novel functionalized pyrrolopyridines in one- and two-step reactions under substitution of the molecular scaffold and the 4-aniline residue, respectively. They were evaluated as inhibitors of Brk and HER2 in a radiolabelled enzyme assay. Results: The most favourable substituents for Brk inhibitory activity at the aniline residues were 3-hydroxy functions combined with either bromo or nitro substituents at the molecular scaffold. Those compounds, as well as bromo- and nitro-substituted compounds, also showed the best HER2 inhibitor activities. Conclusions: Novel pyrrolopyridines were discovered to be a promising class of nanomolar Brk inhibitor with additional HER2 activities to further strengthen Brk inhibitory activity in prospective anticancer therapies. Thus, the first class of Brk inhibitors could be identified.