Work

Targeting Kinase Signaling in Glioblastoma: Structural Optimization, Blood–Brain Barrier Dynamics and Combinatorial Translational Strategies

Year: 2026

Type: article

Abstract: Small-molecule kinase inhibitors offer a compelling therapeutic strategy for glioblastoma, yet their clinical efficacy remains severely limited by blood-brain barrier penetration and active efflux transporter extrusion. This review evaluates current medicinal chemistry approaches and translational paradigms to overcome these drug delivery and biological constraints. A critical analysis of the literature reveals that direct structural optimization faces a multidimensional balancing act; next-generation design must prioritize macrocyclization, structural rigidification, and bioisosteric capping to lower polar surface area and evade P-glycoprotein and BCRP efflux. Furthermore, carrier-mediated prodrugs targeting the LAT1 transporter provide a viable rescue strategy for highly potent scaffolds. Reviewing recent clinical failures, such as paxalisib and osimertinib, underscores that single-node monotherapies fail due to compensatory pathway hyperactivation and clonal heterogeneity, whereas multi-targeted agents or rational dual-node combinations prevent rapid tumor adaptation. Additionally, combining kinase inhibitors with DNA damage repair inhibitors, immune checkpoint modulation, or MR-guided focused ultrasound could provide powerful synergistic networks. Finally, bridging the translational gap requires complementing conventional serum-cultured cell lines with patient-derived glioma stem cells and orthotopic xenografts to better recapitulate the cellular architecture of the disease. Ultimately, overcoming the therapeutic challenges in glioblastoma demands a fundamental pivot toward rigorous neuro-pharmacological design and multi-lineage network oncology.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms27156590

Authors: Diana Juanes-Gusano, Beatriz Fernández-Roldán, Rafael Coveñas, Maruan Hijazi

Institutions: Universidad de Salamanca, Instituto de Investigación Biomédica de Salamanca, Instituto de Neurociencias de Castilla y León

Language: English

Topic: Glioma Diagnosis and Treatment

Subfield: Genetics

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499