Design, synthesis, and anti-glioblastoma multiforme evaluation of novel multikinase inhibitors via a cyclization strategy with potent FAK inhibition

Glioblastoma multiforme (GBM) counts as one of the highly deadly primary intracranial malignancies, posing a significant challenge to clinical management. Focal Adhesion Kinase (FAK) has been identified as a pivotal molecular target implicated in GBM pathogenesis, modulating key processes such as tumor cell proliferation, invasion, and therapeutic resistance. Despite the considerable number of FAK inhibitors advancing to clinical evaluation, their efficacy against GBM remains inadequately documented. In this study, a cyclization strategy was served for discovering novel FAK inhibitors, which was employed TAE-226 as the molecular scaffold. Among the synthesized derivatives, compound 16c distinguished itself as a highly potent inhibitor, showing an IC₅₀ value of 5.8 nM against FAK and robust antiproliferative activities in U87-MG (IC₅₀ = 6.6 nM) and U118-MG (IC₅₀ = 4.3 nM) GBM cell lines. Additionally, 16c exhibited favorable blood-brain barrier penetration, markedly promoted apoptotic cell death, and induced G2/M cell cycle arrest in U87-MG cells. Furthermore, compound 16c exhibited significant inhibitory activity against 25 kinases, which indicated that it could be a promising multi-targeted kinase inhibitor. Importantly, the oral bioavailability of 16c reached 18.7% at a dose of 10 mg/kg, and 16c displayed pronounced antitumor efficacy in the absence of detectable systemic toxicity in a U87-MG xenograft model. These results collectively highlight the promise of FAK inhibition as a therapeutic strategy for GBM.

Design; FAK; GBM; Multikinase; Synthesis.