Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma

The
DYRK family contains kinases that are up-regulated in malignancy
and control several cancer hallmarks. To assess the anticancer potential
of inhibitors targeting DYRK kinases, we developed a series of novel
DYRK inhibitors based on the 7-azaindole scaffold. All compounds were
tested for their ability to inhibit DYRK1A, DYRK1B, DYRK2, and the
structurally related CLK1. The library was screened for anticancer
efficacy in established and stem cell-like glioblastoma cell lines.
The most potent inhibitors (IC50 ≤ 50 nM) significantly
decreased viability, clonogenic survival, migration, and invasion
of glioblastoma cells. Target engagement was confirmed with genetic
knockdown and the cellular thermal shift assay. We demonstrate that
DYRK1A’s thermal stability in cells is increased upon compound
treatment, confirming binding in cells. In summary, we present synthesis,
structure–activity relationship, and efficacy in glioblastoma-relevant
models for a library of novel 7-azaindoles.