Aug 2026· Bioorganic chemistry (Print)· Vol 181, pp.
110370
· 0 citations· 57 references
Medicine
TL;DR
The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression, and highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma.
Abstract
Glioblastoma, the most prevalent and highly aggressive primary brain tumor, is characterized by high clinical recurrence rates and significant resistance to conventional therapies, highlighting the need for innovative targeted agents to address current treatment limitations. This study employed an integrated computational and experimental strategy to identify novel iodo-phenanthroimidazole derivatives (compounds 1-3). Compound 3 was identified as a lead candidate that inhibits HDAC1 and may trigger autophagy, thereby suppressing glioblastoma progression. Molecular docking and molecular dynamics simulations indicated stable interactions between compound 3 and the HDAC1 catalytic site (estimated binding energies of -7.75 and - 7.74 kcal/mol), with a notable halogen bond between the iodine atom and Asp104. The phenanthroimidazole scaffold was proposed as a potential zinc-binding group (ZBG) for HDAC1 inhibition. Biophysical validation using isothermal titration calorimetry (ITC) confirmed submicromolar binding affinity (Kd = 1.04 × 10-7 M, ΔH = -91.24 kJ·mol-1). In vitro evaluation demonstrated potent inhibition of U87-MG glioblastoma cell proliferation (IC50 = 0.23 μM), and flow cytometric analysis indicated concomitant cell cycle arrest at both G2/M and S phases. Transmission electron microscopy revealed autophagic vacuoles containing damaged mitochondria, and immunofluorescence showed an increased LC3-II/LC3-I ratio. Together with the observed loss of mitochondrial membrane potential and ATP depletion, these findings are consistent with the induction of a mitophagy-like process. Using an in vivo zebrafish orthotopic glioblastoma model, the lead compound demonstrated blood-brain barrier penetration and effectively suppressed tumor growth and U87-MG cell metastasis. This work highlights the potential of iodo-phenanthroimidazole derivatives as a novel therapeutic strategy for glioblastoma. The data support a model in which HDAC1 inhibition is associated with mitochondrial dysfunction and mitophagy, contributing to tumor suppression.
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.
Findings highlight Withaferin A as a promising natural inhibitor of UBE2J1 and provide a foundation for future experimental validation aimed at developing targeted therapies against ovarian cancer.
Zujaja Rehman, Ejaz Rasul, Wisha Asif et al.· In Silico Pharmacology· 0 citations
Metabolic reprogramming relying on abnormal glycolysis fuels tumor growth, rendering the rate-limiting glycolytic enzyme PFKL a potential anticancer target; yet no PFKL inhibitor has entered clinical trials. Herein, we synthesized a series of S-benzylisothiourea imidazolium salt derivatives and identified compound 10w, which potently inhibited breast cancer cell proliferation, suppressed glycolysis, and induced apoptosis. Drug Affinity Responsive Target Stability (DARTS) assays revealed PFKL as the direct cellular target of 10w. Surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and molecular docking studies confirmed the binding of 10w to PFKL. Enzymatic activity assays further demonstrated that 10w inhibited PFKL activity. Notably, 10w exerted no obvious effects on glycolysis or glycolytic capacity in PFKL-knockdown breast cancer cells. In vivo assays showed that 10w exerted significant antitumor efficacy and enhanced the efficacy of anti-PD-L1 immunotherapy. In conclusion, compound 10w targets PFKL as a promising therapeutic agent for breast cancer.
Mengqi Wang, Xinge Li, Yan Bai et al.· Journal of Medicinal Chemist...· 0 citations
Cancer remains a major global health challenge, highlighting the need for novel therapeutic agents with improved selectivity and efficacy. Histone deacetylase (HDAC) inhibition represents an important epigenetic strategy in anticancer drug discovery because it can influence gene expression, cell-cycle regulation, and tumor cell survival. In this computational study, fifteen 4-oxoquinazolin-3(4
H
)-yl-
N
-hydroxybenzamide derivatives were evaluated as potential HDAC8-targeting compounds using an integrated
in silico
workflow. Molecular docking was performed against HDAC8 using the crystal structure deposited under Protein Data Bank (PDB) ID 1T69, with suberoylanilide hydroxamic acid (SAHA) used as the reference inhibitor.
The investigated derivatives showed favorable accommodation within the HDAC8 catalytic pocket, with predicted interaction patterns involving zinc coordination, hydrogen bonding, and π-related interactions with key active-site residues. Several derivatives showed favorable predicted docking scores and interaction profiles relative to SAHA, suggesting that the designed quinazolinone–hydroxamate scaffold may be suitable for further prioritization. Prime molecular mechanics generalized Born surface area (MM-GBSA) analysis identified selected derivatives with comparatively favorable calculated binding free-energy contributions, particularly through van der Waals, electrostatic, and lipophilic interactions.
In silico
absorption, distribution, metabolism, and excretion (ADME) prediction indicated that most derivatives possessed acceptable drug-like and pharmacokinetic descriptors, including physicochemical properties, predicted oral absorption, and limited central nervous system (CNS) activity. Density functional theory (DFT) analysis provided supportive electronic-level information by identifying molecular regions that may contribute to hydrogen bonding and zinc coordination. A 100 ns molecular dynamics simulation of the HDAC8–derivative 15 complex suggested the short-timescale persistence of one representative predicted binding pose under the selected simulation conditions.
Overall, this study identifies selected 4-oxoquinazoline hydroxamic acid derivatives as preliminary computational leads for further experimental validation as potential HDAC8-targeting compounds.
D. Saleem, M. Mahdi, Ayad Mohammed Rasheed· Pharmacia· 0 citations
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.
Peroxiredoxin 3 (PRDX3), located in mitochondria, plays a crucial catalytic role in maintaining mitochondrial redox homeostasis and represents a promising target for antitumor drug development. Celastrol is a natural inhibitor of PRDX3; however, it suffers from poor subtype selectivity and high toxicity. In this study, celastrol was used as a lead compound for structural optimization. First, we demonstrated that introducing a triphenylphosphine (TPP) group enables mitochondrial targeting and reduces cytotoxicity. Subsequently, the TPP moiety was exploited as a privileged fragment for further optimization. After two rounds of structural modification, compound 10d was obtained, exhibiting the best antiproliferative activity. Its key structural features include a TPP group attached at the C-3 position and an ethylamine fragment linked at the C-20 position. Compound 10d showed an IC50 value of 0.64 μM against H1975 cells, approximately 3-fold more potent than celastrol. Mechanistic studies revealed that 10d binds to PRDX3 with high affinity (Kd = 0.514 μM), about 17-fold higher than that of celastrol (Kd = 8.56 μM). Furthermore, 10d downregulated the downstream NF-κB and VEGF signaling pathways of PRDX3, effectively suppressing migration and invasion of H1975 cells. In vivo efficacy evaluation demonstrated that 10d exhibited significantly superior tumor suppression in a subcutaneous xenograft model of H1975 tumors compared to celastrol, without causing notable systemic toxicity such as significant body weight loss. In summary, this study successfully developed a highly effective and safe mitochondrially targeted PRDX3 inhibitor, providing a valuable lead compound for the development of innovative drugs targeting tumor redox metabolism.
Yu-Chi Zhao, Hanshuang Cai, Lijuan Zuo et al.· European journal of medicina...· 0 citations