Flexible Analogues of Azaindole DYRK1A Inhibitors Elicit Cytotoxicity in Glioblastoma Cells*

Abstract DYRK1A is a novel target for epidermal growth factor receptor (EGFR)-dependent glioblastoma and it represents a promising strategy for cancer therapy. DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering endocytosis and lysosomal degradation, thus reducing the self-renewal ability of tumorigenic cells. Using a deconstruction approach of a DYRK1A lead molecule DANDY (1a), a set of novel ring-opened compounds was prepared. Despite showing no activity towards DYRK1A, a reduction in the viability of glioblastoma cells was observed with some of the compounds. This suggests other mechanistic pathways are leading to the apoptosis of glioblastoma cells.