---
title: "Novel multikinase FAK inhibitors for glioblastoma: design, cyclization strategy, and preclinical e"
id: "pubmed-42019175"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42019175"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42019175/"
doi: "10.1016/j.ejmech.2026.118877"
published_at: "2026-08-05T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Novel multikinase FAK inhibitors for glioblastoma: design, cyclization strategy, and preclinical e
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42019175
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42019175/)
- **DOI:** [10.1016/j.ejmech.2026.118877](https://doi.org/10.1016%2Fj.ejmech.2026.118877)
- **Published At:** 2026-08-05T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Glioblastoma multiforme (GBM) remains a highly lethal primary brain tumor with limited effective therapies; **Focal Adhesion Kinase (FAK)** is implicated in GBM proliferation, invasion, and therapy resistance and is a rationale therapeutic target. - The study used a **cyclization strategy** based on the TAE-226 scaffold to design and synthesize novel multikinase inhibitors aimed at potent FAK inhibition. - Among synthesized derivatives, **compound 16c** emerged as a lead: FAK IC50 = **5.8 nM**, and potent antiproliferative activity in GBM cell lines U87-MG (IC50 = **6.6 nM**) and U118-MG (IC50 = **4.3 nM**). - Compound 16c showed favorable **blood–brain barrier** penetration in the authors’ evaluation and induced **apoptosis** and **G2/M cell cycle arrest** in U87-MG cells. - Kinase profiling indicated that 16c inhibited **25 kinases**, suggesting a multikinase activity profile rather than strict selectivity for FAK. - Oral pharmacokinetic data reported an oral bioavailability of **18.7%** at 10 mg/kg for 16c. - In a U87-MG xenograft model, 16c produced marked antitumor efficacy without detectable systemic toxicity under the study conditions. - The authors conclude that FAK inhibition via this scaffold and cyclization approach may represent a promising therapeutic strategy for GBM; specific experimental details (full synthetic routes, complete kinase panel list, dosing regimen in vivo) are not reported in the abstract and would require consulting the full text for confirmation.
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Epub 2026 Apr 18. # Design, synthesis, and anti-glioblastoma multiforme evaluation of novel multikinase inhibitors via a cyclization strategy with potent FAK inhibition [Ying Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+Y&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Ting Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+T&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Kehui Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+K&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Daili Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+D&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Yang Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42019175)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-2 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ychen1@gzu.edu.cn."), [Longjia Yan](https://pubmed.ncbi.nlm.nih.gov/?term=Yan+L&cauthor_id=42019175)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#full-view-affiliation-3 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ylj1089@gzu.edu.cn.") Affiliations Expand ### Affiliations * 1 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. * 2 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ychen1@gzu.edu.cn. * 3 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ylj1089@gzu.edu.cn. * PMID: **42019175** * DOI: [ 10.1016/j.ejmech.2026.118877 ](https://doi.org/10.1016/j.ejmech.2026.118877) Item in Clipboard # Design, synthesis, and anti-glioblastoma multiforme evaluation of novel multikinase inhibitors via a cyclization strategy with potent FAK inhibition Ying Xu et al. Eur J Med Chem. 2026. Show details Display options Display options Format Abstract PubMed PMID Eur J Med Chem Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Eur+J+Med+Chem%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Eur+J+Med+Chem%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42019175/) . 2026 Aug 5:312:118877. doi: 10.1016/j.ejmech.2026.118877. Epub 2026 Apr 18. ### Authors [Ying Xu](https://pubmed.ncbi.nlm.nih.gov/?term=Xu+Y&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Ting Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+T&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Kehui Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+K&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Daili Wu](https://pubmed.ncbi.nlm.nih.gov/?term=Wu+D&cauthor_id=42019175)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-1 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China."), [Yang Chen](https://pubmed.ncbi.nlm.nih.gov/?term=Chen+Y&cauthor_id=42019175)[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-2 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ychen1@gzu.edu.cn."), [Longjia Yan](https://pubmed.ncbi.nlm.nih.gov/?term=Yan+L&cauthor_id=42019175)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42019175/#short-view-affiliation-3 "School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ylj1089@gzu.edu.cn.") ### Affiliations * 1 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. * 2 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ychen1@gzu.edu.cn. * 3 School of Pharmaceutical Sciences, Guizhou University, Guiyang, 550025, China. Electronic address: ylj1089@gzu.edu.cn. * PMID: **42019175** * DOI: [ 10.1016/j.ejmech.2026.118877 ](https://doi.org/10.1016/j.ejmech.2026.118877) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract 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. **Keywords:** Design; FAK; GBM; Multikinase; Synthesis. Copyright © 2026 Elsevier Masson SAS. All rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ## Similar articles * [ Discovery of a macrocyclic FAK inhibitor GZD-257 for treatment of glioblastoma. ](https://pubmed.ncbi.nlm.nih.gov/41045971/) Wu T, Zuo Y, Chen K, Xu Y, Wu D, Le Y, Liu L, Yan L.Wu T, et al.Bioorg Med Chem Lett. 2026 Jan 1;130:130424. doi: 10.1016/j.bmcl.2025.130424. Epub 2025 Oct 2.Bioorg Med Chem Lett. 2026.PMID: 41045971 * [ Discovery of noncovalent diaminopyrimidine-based Inhibitors for glioblastoma via a dual FAK/DNA targeting strategy. ](https://pubmed.ncbi.nlm.nih.gov/39832391/) Wei Y, He X, Long Z, Le Y, Liu L, Yan L.Wei Y, et al.Eur J Med Chem. 2025 Mar 15;286:117288. doi: 10.1016/j.ejmech.2025.117288. Epub 2025 Jan 16.Eur J Med Chem. 2025.PMID: 39832391 * [ Discovery of novel pyrrolo [2,3-d] pyrimidine derivatives as potent FAK inhibitors based on cyclization strategy. ](https://pubmed.ncbi.nlm.nih.gov/37459823/) Zeng S, Yuan S, Zhang Y, Du J, Wu Y, Chen Y, Zhu P, Huang W.Zeng S, et al.Bioorg Chem. 2023 Oct;139:106713. doi: 10.1016/j.bioorg.2023.106713. Epub 2023 Jul 7.Bioorg Chem. 2023.PMID: 37459823 * [ Discovery of potent focal adhesion kinase (FAK) inhibitor A8 with enhanced antitumor activity. ](https://pubmed.ncbi.nlm.nih.gov/40239484/) Li Y, He Y, Zhang C, Gan L, Zhang H.Li Y, et al.Eur J Med Chem. 2025 Jul 5;291:117593. doi: 10.1016/j.ejmech.2025.117593. Epub 2025 Apr 4.Eur J Med Chem. 2025.PMID: 40239484 * [ Molecular hybridization-driven FAK inhibitors: N-2,4-diarylaminopyrimidine-3-sulfamoyl-benzamide derivatives with improved antitumor potency. ](https://pubmed.ncbi.nlm.nih.gov/40578255/) Gong L, Liang Z, Ning X, He J, Huang J, Li R, Yin Y, Li R, Lin Z.Gong L, et al.Eur J Med Chem. 2025 Oct 15;296:117885. doi: 10.1016/j.ejmech.2025.117885. 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