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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Small-molecule kinase inhibitors offer a compelling therapeutic strategy for glioblastoma, yet their clinical efficacy remains severely limited by blood\u2013brain 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.<\/jats:p>","DOI":"10.3390\/ijms27156590","type":"journal-article","created":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T10:38:41Z","timestamp":1784889521000},"page":"6590","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting Kinase Signaling in Glioblastoma: Structural Optimization, Blood\u2013Brain Barrier Dynamics and Combinatorial Translational Strategies"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5818-7371","authenticated-orcid":false,"given":"Diana","family":"Juanes-Gusano","sequence":"first","affiliation":[{"name":"Group USAL-BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Neuroscience of Castilla and Le\u00f3n (INCyL), iBRAINS-IN-CyL, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1528-466X","authenticated-orcid":false,"given":"Beatriz","family":"Fern\u00e1ndez-Rold\u00e1n","sequence":"additional","affiliation":[{"name":"Group USAL-BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Neuroscience of Castilla and Le\u00f3n (INCyL), iBRAINS-IN-CyL, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5677-8266","authenticated-orcid":false,"given":"Rafael","family":"Cove\u00f1as","sequence":"additional","affiliation":[{"name":"Group USAL-BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Neuroscience of Castilla and Le\u00f3n (INCyL), iBRAINS-IN-CyL, 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0861-7577","authenticated-orcid":false,"given":"Maruan","family":"Hijazi","sequence":"additional","affiliation":[{"name":"Group USAL-BMD (Bases Moleculares del Desarrollo), University of Salamanca, 37007 Salamanca, Spain"},{"name":"Institute of Neuroscience of Castilla and Le\u00f3n (INCyL), iBRAINS-IN-CyL, 37007 Salamanca, Spain"},{"name":"Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1231","DOI":"10.1093\/neuonc\/noab106","article-title":"The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary","volume":"23","author":"Louis","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Brar, H.K., Jose, J., Wu, Z., and Sharma, M. 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