Design Synthesis and Biological Evaluation of DYRK1A Inhibitors

Abstract

DYRK1A is a dual-specificity protein kinase that catalyses not only autophosphorylation on its tyrosine residue but the phosphorylation of serine and threonine residues in its substrates. DYRK1A has been shown to be important for phosphorylation of tau protein and has also been identified as a Down syndrome candidate gene. DYRK1A overexpression has also been found in cancer cells, particularly in glioblastoma, which represents 15% of brain tumours. The increased phosphorylation of sprouty2 mediated by DYRK1A blocks the EGFR degradation as a result of overexpression of EGFR in the cell surface, and the enhanced EGFR signalling eventually leads to tumour survival. On the contrary, DYRK1A inhibition has been found to promote EGFR degradation in glioblastoma cells by triggering the endocytosis and lysosomal degradation, thus reducing the self-renewal ability of tumourigenic cells. Development of small molecule inhibitors of DYRK1A therefore provides attractive treatment strategies. A recently discovered lead compound, DANDY represents one chemotype of the most potent DYRK1A inhibitors. The work in this thesis explores the importance of the 7-azaindole skeleton to DYRK1A inhibition through the systematic modification to structural features of DANDY. The sequential selectivity of promising inhibitors over other off-targets such as DYRK1B, DYRK2 and CLK1, as well as the functional activity against glioblastoma cells has also been explored. Preliminary kinase inhibition assays together with cell viability assays have shown promising trends towards the correlation between DYRK1A inhibition activities and cellular efficacies in vitro. In this thesis, several promising compounds have shown inhibition for DYRK1A with IC50 values being < 50 nM. These compounds have also played effective roles for the in vitro treatment of glioblastoma cell viability assays.