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

Qingqing Zhou, Athena F Phoa, Ramzi H. Abbassi, Monira Hoque, Tristan A. Reekie, Josep S. Font, Renae M Ryan, Brett William Stringer, Bryan W Day, Terrance G. Johns, Lenka Munoz, Michael Kassiou

Research output: Contribution to journalArticleResearchpeer-review

22 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2052-2070
Number of pages19
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - 9 Mar 2017
Externally publishedYes

Cite this