title: Structural Optimization and Pharmacological Evaluation of Inhibitors Targeting Dual-Specificity Tyrosine Phosphorylation-Regulated Kinases (DYRK) and CDC-like kinases (CLK) in Glioblastoma.
abstract: 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.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Zhou
authors.forename: Athena F
authors.initials: AF
authors.lastname: Phoa
authors.forename: Ramzi H
authors.initials: RH
authors.lastname: Abbassi
authors.forename: Monira
authors.initials: M
authors.lastname: Hoque
authors.forename: Tristan A
authors.initials: TA
authors.lastname: Reekie
authors.forename: Josep S
authors.initials: JS
authors.lastname: Font
authors.forename: Renae M
authors.identifier: 0000-0002-8680-4610
authors.initials: RM
authors.lastname: Ryan
authors.affiliation: QIMR Berghofer Medical Research Institute , 300 Herston Road, Herston, Queensland 4006, Australia.
authors.forename: Brett W
authors.initials: BW
authors.lastname: Stringer
authors.affiliation: QIMR Berghofer Medical Research Institute , 300 Herston Road, Herston, Queensland 4006, Australia.
authors.forename: Bryan W
authors.initials: BW
authors.lastname: Day
authors.affiliation: Oncogenic Signaling Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research , 27 Wright Street, Clayton, Victoria 3168, Australia.
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Lenka
authors.identifier: 0000-0002-7625-5646
authors.initials: L
authors.lastname: Munoz
authors.forename: Michael
authors.identifier: 0000-0002-6655-0529
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D001932:Brain Neoplasms / Q000201:enzymology*; D005909:Glioblastoma / Q000201:enzymology*; D006801:Humans; D010766:Phosphorylation; D011494:Protein Kinases / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000378:metabolism*
chemical_list: D014443:Tyrosine; D011494:Protein Kinases