Glioblastoma (GBM) poses a severe threat to the health of the central nervous system. Among the existing therapeutic agents, the primary chemotherapeutic drug temozolomide is constrained by drug resistance. Thus, the development of new drugs for GBM treatment is urgently needed. Given that focal adhesion kinase (FAK) is highly associated with the occurrence and progression of GBM, this study conducted a scaffold hopping using TAE‐226 (The first approved FAK inhibitor and failed in phase II) as the parent nucleus to design and synthesize a series of diaminopyrimidine derivatives. Activity screening results showed that compounds
5f
and
5o
showed potent activity against U118‐MG cells with IC
50
values of 0.29 µM and 0.41 µM, as well as inhibited FAK kinase with IC
50
values of 10.23 and 11.87 nM, respectively. Further mechanistic studies demonstrated that both compounds could significantly induce cell cycle arrest of U118‐MG cells at the G2/M phase (7.84%–78.09%), effectively promote cancer cell apoptosis, and thereby block their unlimited proliferation. Molecular docking experiments further verified the mechanism underlying the high activity of these two compounds at the molecular level, providing an important structural basis and experimental evidence for the development of new molecules for GBM treatment.
Glioblastoma multiforme (GBM) remains a challenging brain tumor, necessitating innovative therapeutic approaches. Targeting histone deacetylase 6 (HDAC6), a cytosolic isoform implicated in oncogenic pathways, represents a promising strategy with a potentially improved safety profile. In this study, a novel series of derivatives were designed and synthesized as HDAC6 inhibitors based on the phenothiazine scaffold. Among them, compound 6d exhibited potent inhibitory activity, displaying nanomolar inhibition of HDAC6 (IC₅₀ = 0.074 μM) with a high selectivity index of 52.4 over HDAC1, which significantly exceeds the positive control SAHA. Moreover, 6d effectively inhibited the proliferation of U87-MG glioma cells (IC₅₀ = 2.65 μM) and triggered dose-dependent apoptosis and G2/M phase cell cycle arrest, with superior efficacy compared to SAHA. Favorable in silico ADMET properties supported its drug-like potential. Molecular docking and molecular dynamics simulations preliminarily predicted the binding pattern of 6d toward HDAC6. The simulated trajectory parameters exhibited partial convergence throughout the simulation period, indicating tentative intermolecular interactions including hydrophobic contacts, hydrogen bonds, and π-π stacking, rather than fully stable binding. Collectively, these findings confirm that compound 6d is a potential HDAC6 inhibitor and a promising lead for the development of novel anti-GBM therapeutics.