Discovery of Potent Multikinase Type-II Inhibitors Targeting CDK5 in the DFG-out Inactive State with Promising Potential against Glioblastoma

• Published in: Journal of medicinal chemistry 2024-05, Vol.67 (9), p.7539-7552
• Main Authors: Khan, Zahra R., Welsby, Philip J., Stasik, Izabela, Hayes, Joseph M.
• Format: Article
• Language: English
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.4c00373

Kinases have proven valuable targets in successful cancer drug discovery projects, but not yet for malignant brain tumors where type-II inhibition of cyclin-dependent kinase 5 (CDK5) stabilizing the DFG-out inactive state has potential for design of selective and clinically efficient drug candidates. In the absence of crystallographic evidence for a CDK5 DFG-out inactive state protein–ligand complex, for the first time, a model was designed using metadynamics/molecular dynamics simulations. Glide docking of the ZINC15 biogenic database identified [pyrimidin-2-yl]­amino-furo­[3,2-b]-furyl-urea/amide hit chemical scaffolds. For four selected analogues (4, 27, 36, and 42), potent effects on glioblastoma cell viability in U87-MG, T98G, and U251-MG cell lines and patient-derived cultures were generally observed (IC50s ∼ 10–40 μM at 72 h). Selectivity profiling against 11 homologous kinases revealed multikinase inhibition (CDK2, CDK5, CDK9, and GSK-3α/β), most potent for GSK-3α in the nanomolar range (IC50s ∼ 0.23–0.98 μM). These compounds may therefore have diverse anticancer mechanisms of action and are of considerable interest for lead optimization.