Drug Development Research[JOURNAL]
Sun
200 papers
Mesalamine in Treatment of Intestinal Inflammatory Diseases-Formulation-Driven Strategies for Targeted Colonic Therapy and Remission Maintenance.
Sahoo B, Patel J
Drug Dev Res · 2026 Jun · PMID 42163435 · Publisher ↗
Mesalamine (5‑aminosalicylic acid, mesalazine, or 5‑ASA) remains a cornerstone therapy for mild‑to‑moderate ulcerative colitis because of its local anti‑inflammatory and antioxidant actions on the intestinal mucosa, and...
Mesalamine (5‑aminosalicylic acid, mesalazine, or 5‑ASA) remains a cornerstone therapy for mild‑to‑moderate ulcerative colitis because of its local anti‑inflammatory and antioxidant actions on the intestinal mucosa, and its clinical performance has increasingly been refined through advances in synthetic medicinal chemistry and drug‑delivery science. Beyond conventional formulations, medicinal chemistry efforts have explored mesalamine analogues and hybrid molecules, including prodrug approaches and conjugates with anti‑inflammatory or redox‑modulating moieties, to extend target engagement beyond classical cyclooxygenase inhibition toward pathways such as oxidative stress regulation and inflammasome signaling, thereby offering the potential for synergistic, multi‑pathway control of mucosal inflammation. In parallel, nanoparticle‑based delivery systems-such as pH‑responsive polymeric nanoparticles, mucoadhesive nanocarriers, and multi‑matrix or hydrogel‑based platforms-have been developed to protect mesalamine from premature upper gastrointestinal absorption, exploit disease‑associated pH and permeability changes, and prolong residence time at inflamed colonic sites, resulting in higher local drug concentrations with reduced systemic exposure. These strategies complement established oral and topical formulations and combination regimens, with preclinical and early translational data suggesting improvements in mucosal healing, attenuation of oxidative injury, and enhanced adherence through simplified dosing. When viewed together with emerging combination strategies that pair mesalamine with agents such as budesonide, sucralfate, or antioxidant and immunomodulatory compounds, these advances underscore a broader shift toward precision‑designed mesalamine therapies, integrating molecular optimization and targeted delivery to improve clinical outcomes in ulcerative colitis and to support exploratory roles in related inflammatory enteropathies.
TRIM26-Mediated CBX6 Ubiquitination Triggers NETosis to Drive Bladder Cancer Tumor Growth via the CNPY2/NF-κB Signaling Pathway.
Xie X, Li Z, Qiu T … +2 more , Li H, Gui Q
Drug Dev Res · 2026 Jun · PMID 42163428 · Publisher ↗
Neutrophil extracellular traps (NETs) play a critical role in bladder cancer (BCa) progression, but the intrinsic molecular drivers within tumor cells that orchestrate NET formation remain largely unknown. This study aim...
Neutrophil extracellular traps (NETs) play a critical role in bladder cancer (BCa) progression, but the intrinsic molecular drivers within tumor cells that orchestrate NET formation remain largely unknown. This study aimed to investigate whether and how the E3 ubiquitin ligase TRIM26 influences BCa malignancy by regulating NET formation. Analysis of public cohort data revealed a significant positive correlation between TRIM26 expression and neutrophil infiltration in BCa, which was confirmed in our clinical samples showing markedly enhanced neutrophil infiltration and NET formation in tumor tissues compared with adjacent normal tissues. Functional assays demonstrated that NETs promoted BCa cell proliferation, migration, invasion, and epithelial-mesenchymal transition in a TRIM26‑dependent manner. Mechanistically, TRIM26 directly bound to Chromobox 6 (CBX6) and mediated its ubiquitination and degradation. CBX6 transcriptionally represses canopy FGF signaling regulator 2 (CNPY2) by catalyzing H2AK119ub1 deposition on its promoter. Degradation of CBX6 led to CNPY2 upregulation, which activated the NF‑κB pathway and stimulated IL‑8 secretion. Secreted IL‑8 recruited neutrophils and induced NET formation, establishing a positive feedback loop that fuels tumor progression. In vivo experiments confirmed that disrupting NETs with DNase I significantly inhibited TRIM26 overexpression‑driven tumor growth and metastasis. Collectively, this study uncovers a TRIM26/CBX6/CNPY2 signaling axis that drives NET formation via the NF-κB/IL-8 pathway to promote BCa progression, providing novel mechanistic insights and potential therapeutic targets for combating NET-driven BCa malignancy.
Kv1.3 Channel Blockade by Dalfampridine Attenuates NLRP3 Inflammasome-Driven Demyelination via the NEK7/Ripk1/FADD Pathway, Matching the Efficacy of Broad P2X7 Antagonism by Suramin in EAE.
Kamel AS, Shalaby HN, El-Said YAM … +1 more , Nawwar DA
Drug Dev Res · 2026 May · PMID 42145136 · Publisher ↗
The loss of intracellular K facilitated by different channels such as Panx1, TWIK2, or Kv1.3, is a danger signal that activates programmed cell death in oligodendrocytes via NLRP3 inflammasome and pyroptosis in multiple...
The loss of intracellular K facilitated by different channels such as Panx1, TWIK2, or Kv1.3, is a danger signal that activates programmed cell death in oligodendrocytes via NLRP3 inflammasome and pyroptosis in multiple sclerosis (MS). ATP triggers P2X7 purinergic receptors, which coordinate TWIK-2 and Panx-1 channels. Given this hierarchical signaling architecture, the present study postulated that strategic Kv1.3 intervention using Dalfampridine (Dal) could mirror comprehensive P2X7 blockade with Suramin (Sur) in the experimental autoimmune encephalomyelitis (EAE) as MS animal model. EAE mice received either Dal (10 µg/mouse/day, oral for 2 weeks) or a single Sur injection (100 mg/kg, intraperitoneal). Both interventions demonstrated comparable efficacy in restoring motor function in open field and rotarod tests, preserving myelin integrity under Luxol fast blue stain, and attenuating neuroinflammatory infiltrates within spinal tissues. Molecular profiling confirmed EAE-associated hyperactivation of the ATP-P2X7R-K⁺ efflux cascade. Sur exerted broad-spectrum inhibition, suppressing ATP accumulation, P2X7R overexpression, and all three channels. Conversely, Dal specifically reduced Kv1.3 expression while leaving ATP levels, P2X7R, TWIK-2, and pannexin-1 unchanged. Remarkably, both compounds achieved equivalent disruption of NEK7/Ripk1/FADD/NLRP3 inflammasome complex and pyroptotic machinery, including pro-caspas1 activation and subsequent gasdermin-D cleavage. These findings suggest that Kv1.3 may serve as a contributory node where downstream channel modulation can deliver neuroprotection equivalent to the upstream pathway intervention. By modulating this potential checkpoint, Kv1.3-targeted therapy may reduce collateral effects associated with pan-purinergic blockade, offering a potential streamlined therapeutic corridor for demyelinating neuroinflammation with enhanced specificity and reduced systemic burden.
MORC2 Recruits Tumor-Associated Macrophages and Inhibits Pyroptosis Through Activating the Wnt/β-Catenin Pathway in Breast Cancer.
Liu Z, Hu H, Lin Z … +1 more , Meng X
Drug Dev Res · 2026 May · PMID 42145133 · Publisher ↗
Breast cancer (BC), characterized by a high incidence specifically in women, exhibits a complex etiology. This study aims to investigate the role and underlying mechanism of microrchidia CW-type zinc finger 2 (MORC2) in...
Breast cancer (BC), characterized by a high incidence specifically in women, exhibits a complex etiology. This study aims to investigate the role and underlying mechanism of microrchidia CW-type zinc finger 2 (MORC2) in BC progression. MCF-7 and MDA-MB-231 cells with MORC2 knockdown were utilized to investigate the impact of MORC2 on BC. To explore the in vivo functions of MORC2, xenograft tumor mouse model was established. In this study, we discovered that MORC2 was significantly upregulated in BC tumor tissues. Consistent with MORC2 functioning as a suppressor of pyroptosis, MORC2 knockdown enhanced the expression of pyroptosis-related markers (Caspase-1, NLRP3, GSDMD-N, and LDH) and inflammatory factors (IL-18, IL-1β, and TNF-α), while suppressing CCL5, CCL2 levels, and macrophage migration. Furthermore, MORC2 knockdown inhibited tumor growth in vivo, decreased CD68 cell infiltration and M2 markers, and increased the M1/M2 macrophage ratio. TAMs from MORC2-knockdown tumors exhibited reduced immunosuppressive capacity, promoting T cell proliferation and IFN-γ/IL-2 production. Mechanistically, silencing of MORC2 suppressed the Wnt/β-catenin pathway, and Compound 3 f significantly reversed the effects of MORC2 knockdown on pyroptosis and macrophage recruitment BC. In summary, MORC2 suppresses pyroptosis and promotes TAMs recruitment in BC; MORC2 knockdown alleviated the progression of BC by reversing these effects, which was mediated by suppressing the Wnt/β-catenin signaling pathway.
Potential Biological Targets of Anticancer Metal-Based Drug Candidates: A Systematic Review.
Ferreira ALDS, Dantas BB, Souza-Ferrari J … +1 more , Filho EBA
Drug Dev Res · 2026 May · PMID 42145117 · Full text
The discovery of Cisplatin marked the beginning of the metallodrug era in oncology. Despite their clinical success, platinum-based compounds present important limitations, including drug resistance and systemic toxicity....
The discovery of Cisplatin marked the beginning of the metallodrug era in oncology. Despite their clinical success, platinum-based compounds present important limitations, including drug resistance and systemic toxicity. These challenges have stimulated interest in alternative metal complexes capable of interacting with biomolecular targets beyond DNA, particularly proteins involved in cancer-related pathways. To systematically identify and categorize protein targets associated with the antitumor activity of metal complexes in preclinical studies, emphasizing their functional classification and biological relevance. A systematic search was conducted in Web of Science, Wiley, Scopus, and ScienceDirect for studies published between January 2015 and March 2025. Original studies evaluating the antitumor activity of metal complexes with experimental or computational evidence of protein-directed mechanisms were included. Reviews, editorials, theoretical studies without experimental support, and studies focused exclusively on serum albumin binding were excluded. Of the 873 records identified, 59 studies met the inclusion criteria. Reported targets were organized according to Gene Ontology-based biological processes, revealing recurrent associations with redox regulation, apoptosis and cell-cycle control, and DNA replication and repair, with fewer studies addressing angiogenesis and drug-resistance mechanisms. Across categories, mechanistic evidence is predominantly derived from in vitro assays and computational analyses, with limited demonstration of selective intracellular target engagement. Current evidence indicates that metal complexes frequently perturb survival-related cellular networks, particularly those associated with redox balance and stress-response pathways. However, the available literature remains largely preclinical and mechanistically heterogeneous, highlighting the need for more rigorous target-validation strategies to clarify the therapeutic relevance of proposed protein targets.
Programmable Poly-Lactic-Co-Glycolic Acid Nanocarriers for Precision Therapy of Pancreatic Ductal Adenocarcinoma.
Gupta S, Nasir N, Wahab S … +3 more , Gupta G, Goh KW, Kesharwani P
Drug Dev Res · 2026 May · PMID 42121392 · Publisher ↗
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by late-stage diagnosis, dense desmoplastic stroma, rapid metastatic progression, and poor responsiveness to conventional...
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, characterized by late-stage diagnosis, dense desmoplastic stroma, rapid metastatic progression, and poor responsiveness to conventional chemotherapy. Consequently, the development of effective drug delivery strategies capable of overcoming stromal and resistance barriers remains an urgent clinical priority. Poly (lactic-co-glycolic acid) (PLGA) nanoparticles have emerged as a versatile biomaterials platform for improving therapeutic outcomes through enhanced drug solubility, sustained release, and favorable pharmacokinetics. This review critically examines recent advances in the rational design and functionalization of PLGA-based nanocarriers for PDAC therapy, with particular emphasis on tumor-targeted delivery, stromal modulation, and strategies to overcome multidrug resistance. Surface engineering approaches, including ligand conjugation and stimuli-responsive systems, have shown considerable promise in enhancing intratumoral penetration and therapeutic efficacy. In addition, advanced nanoscale analytical and interfacial characterization techniques such as dynamic light scattering, electron microscopy, and zeta potential analysis provide important mechanistic insights into particle stability, cellular interactions, and drug-polymer dynamics, thereby guiding formulation optimization. Collectively, current evidence highlights the strong translational potential of PLGA nanocarriers in precision oncology for PDAC. Continued integration of biomaterials engineering with disease-specific targeting and rigorous physicochemical characterization will be essential to accelerate clinical development and improve patient outcomes.
Astragaloside IV Enhances Anti-PD-L1 Immunotherapy in Triple-Negative Breast Cancer by Activating the cGAS-STING Pathway.
Wei C, Zhang Q, Mao A … +4 more , Pan G, Liu J, Fan X, Li H
Drug Dev Res · 2026 May · PMID 42121378 · Publisher ↗
Astragaloside IV (AS-IV), a natural compound from traditional Chinese medicine, has demonstrated anti-tumor properties. This study aims to explore its potential to enhance anti-mPD-L1 immunotherapy in triple-negative bre...
Astragaloside IV (AS-IV), a natural compound from traditional Chinese medicine, has demonstrated anti-tumor properties. This study aims to explore its potential to enhance anti-mPD-L1 immunotherapy in triple-negative breast cancer (TNBC) by modulating the tumor immune microenvironment. Flow cytometry and immunofluorescence staining analyses were employed to evaluate the influence of AS-IV on cell cycle distribution, apoptosis and DNA damage (phospho-γH2AX staining). The antitumor effects of AS-IV, anti-mPD-L1, or their combination were further investigated using a 4T1 murine breast cancer model. Immune cell infiltration within the tumor tissue was assessed by flow cytometry. AS-IV significantly triggered apoptosis, G0-G1 cell cycle arrest, as well as induced DNA damage and activation of the cGAS-STING pathway in MDA-MB-231 and 4T1 cells. Interestingly, AS-IV notably elevated PD-L1 levels both in two TNBC cells. In vivo experiments indicated that AS-IV treatment notably suppressed tumor growth and triggered tumor cell apoptosis. Meanwhile, AS-IV enhanced anti-tumor efficacy of anti-mPD-L1 on 4T1 murine model, as evidenced by increased infiltration of CD8⁺T cells and elevated secretion of IFN-β, CCL5, and CXCL10. AS-IV remodeled the tumor immune microenvironment and induced PD-L1 upregulation, thereby potentiating the efficacy of anti-mPD-L1 immunotherapy. These findings suggest that AS-IV may serve as a promising immunomodulatory adjuvant in cancer immunotherapy for TNBC.
Heterocyclic Scaffold Modification of Chalcones: Piperidinyl and Morpholinyl Triazene Derivatives as Potent Blood Stage Antimalarials With SAR and Docking Insights.
Thottasseri AA, Rajendran V, Ramesh D … +4 more , Tom AA, Vk A, Das T, Kannan T
Drug Dev Res · 2026 May · PMID 42121371 · Publisher ↗
The emergence of resistance to existing antimalarials, including artemisinin and its combinations, has intensified the need for new chemotypes with improved efficacy. In this study, a scaffold-hopping strategy was employ...
The emergence of resistance to existing antimalarials, including artemisinin and its combinations, has intensified the need for new chemotypes with improved efficacy. In this study, a scaffold-hopping strategy was employed to design and develop two series of triazene-appended chalcones, piperidinyl (PiCs) and morpholinyl (MCs), by modifying our previously reported pyrrolidinyl chalcones (PCs). Both PiC and MC series exhibited moderate to good antimalarial activity, with several derivatives showing improved potency over the parent PCs against the Plasmodium falciparum 3D7 strain. Among them, MC-22 and MC-23 were the most active, exhibiting IC values of 1.02 and 1.13 µg/mL, respectively, while PiC-5, PiC-22, and PiC-18 also demonstrated promising activity (IC = 3.27 to 4.60 µg/mL). Structure-activity relationship analysis highlighted enhanced activity of ortho and meta-substituted derivatives, with the exception of para-CF analogues. Molecular docking confirmed favourable interactions with Plasmodium falciparum-dihydrofolate reductase, and all the hit compounds were found to be non-hemolytic. These findings highlight the effectiveness of heterocyclic scaffold modification in enhancing antiplasmodial activity and demonstrate the potential of morpholine-based triazene-chalcones as promising antimalarial agents.
Unraveling Key Genes Related to Fatty Acid Metabolism in Neuropathic Pain.
Wang Y, Liu C, Wang M … +2 more , Wang Y, Zhou Y
Drug Dev Res · 2026 May · PMID 42117748 · Publisher ↗
Neuropathic pain (NP), a chronic condition resulting from nerve injury or dysfunction, represents considerable therapeutic difficulties owing to its intricate and multifactorial pathophysiology. Recent studies indicate t...
Neuropathic pain (NP), a chronic condition resulting from nerve injury or dysfunction, represents considerable therapeutic difficulties owing to its intricate and multifactorial pathophysiology. Recent studies indicate that dysregulated fatty acid metabolism (FAM) plays a pivotal role in the onset and persistence of NP. Nonetheless, the molecular mechanisms underpinning this association remain incompletely elucidated. This research aims to characterize the expression profiles of FAM-related genes in NP and explore their relationship with immune cell infiltration (ICI). Publicly available gene expression data sets (GSE24982 and GSE2884) were analyzed using bioinformatics approaches to identify differentially expressed genes (DEGs) related to FAM in NP. Differential expression analysis was performed using the limma package in R. Functional enrichment analyses, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA), were carried out to elucidate relevant biological pathways. ICI was assessed using computational deconvolution methods. Overall, 116 FAM-related DEGs were identified in NP. Enrichment analyses highlighted key pathways such as FAM, arachidonic acid metabolism, and the PPAR signal transduction. Among these, Cyp3a2, Hadha, and Scp2 emerged as key genes potentially involved in NP pathogenesis, with Cyp3a2 exhibiting high mRNA levels in validated animal models. ICI analysis revealed significant correlations between the expression of these genes and various immune cell populations, including activated B cells and CD8 T cells, indicating a strong inflammatory component in NP. Moreover, stratification by FAM scores demonstrated distinct gene expression and immune infiltration profiles between low- and high-risk groups. This study highlights the essential role of FAM in the molecular landscape of NP and identifies Cyp3a2, Hadha, and Scp2 as potential biomarkers or therapeutic targets. These findings advance our understanding of NP pathogenesis and offer insights into novel strategies for its management.
Dual-Function Lipid-Based Nanovector Strategy for Glioblastoma Immunotherapy: STING Activation and M1 Microglia Polarization.
Nafie MS, Diab MK, Fahmy SA
Drug Dev Res · 2026 May · PMID 42116763 · Full text
Glioblastoma (GBM) remains one of the most lethal brain malignancies because of its highly immunosuppressive tumor microenvironment and the limited penetration of therapeutics across the blood-brain barrier (BBB). Althou...
Glioblastoma (GBM) remains one of the most lethal brain malignancies because of its highly immunosuppressive tumor microenvironment and the limited penetration of therapeutics across the blood-brain barrier (BBB). Although recent studies have separately explored STING agonism, microglial reprogramming, and nanocarrier-based drug delivery, an integrated framework combining these strategies for GBM immunotherapy is still lacking. In this review, we present a new dual-function lipid-based nanovector (LNV) strategy that simultaneously activates the cGAS-STING pathway and induces tumor-associated microglia to repolarize toward the antitumor M1 phenotype. In contrast to previous reviews, which address them as individual approaches, herein we consolidate these into an integrated therapeutic paradigm and provide a rational design roadmap based on drug cargo selection, lipid isoform composition, BBB targeting, and thermo-/magnetically responsive release. We summarize how STING activation enhances type I interferon signaling, dendritic cell maturation, and cytotoxic T-cell priming, while M1-polarized microglia potentiate local inflammatory and phagocytic antitumor responses. In addition, we summarize the current nanocarrier platforms, preclinical evidence, and translational design considerations pertinent to this combinatorial approach. This review provides a conceptually integrated overview of the potential of dual-action lipid nanovectors to overcome clinically relevant immunological and delivery barriers in GBM, as well as future directions for next-generation nano-immunotherapies.
Nanoplatform-Based Delivery Systems for PROTACs.
Che W, Wang X, Chen S … +8 more , Du M, Wang W, Liu D, Fan S, Wu Z, Wu Y, Dong Y, Xia Q
Drug Dev Res · 2026 May · PMID 42116751 · Publisher ↗
Proteolysis Targeting Chimera (PROTAC) is a bifunctional small molecule composed of a ligand for the target protein, a ligand for an E3 ubiquitin ligase, and a chemical linker. It induces the formation of a ternary compl...
Proteolysis Targeting Chimera (PROTAC) is a bifunctional small molecule composed of a ligand for the target protein, a ligand for an E3 ubiquitin ligase, and a chemical linker. It induces the formation of a ternary complex between the target protein and the E3 ligase, thereby promoting ubiquitination and subsequent proteasomal degradation of the target. As an emerging targeted protein degradation (TPD) strategy, PROTACs offer notable advantages such as rapid action, sustained efficacy, and high selectivity. However, PROTACs encounter significant challenges in in vivo delivery due to their unfavorable physicochemical properties, including high molecular weight, limited membrane permeability, and poor plasma stability. In recent years, the development of nanodelivery platforms has emerged as a promising strategy to overcome these limitations, significantly enhancing the bioavailability and therapeutic efficiency of PROTACs while accelerating their clinical translation and application.
Pyrimidine-Derived Scaffolds Targeting VEGFR-2, EGFR, and HER-2: Synthesis, Anticancer/Immunomodulatory Evaluation, and In Silico Analysis.
Ahmed NM, Gaballah MS, Altava B … +1 more , Lotfallah AH
Drug Dev Res · 2026 May · PMID 42116746 · Publisher ↗
Following the common structural features of VEGFR-2, EGFR, and HER-2 kinase inhibitors, two newly synthesized series of 3,4-dihydropyrimidine 2(1H)-(thio)ones-5-carboxamide (2a-l) and thiouracil-5-sulfonyl derivatives (4...
Following the common structural features of VEGFR-2, EGFR, and HER-2 kinase inhibitors, two newly synthesized series of 3,4-dihydropyrimidine 2(1H)-(thio)ones-5-carboxamide (2a-l) and thiouracil-5-sulfonyl derivatives (4a-e) were evaluated for anti-proliferative activity against colorectal (HCT-116) and breast (MCF-7) cancer cell lines. Among the designed series, Compounds 2h and 2l were the most potent derivatives across both tumor models, exhibiting IC values of 23.3 and 30.9 μM (HCT-116), respectively, and 31.5 and 39.2 μM (MCF-7), respectively, compared to sorafenib (IC = 8.8 and 11.6 μM, respectively). Interestingly, 2h and 2l displayed a favorable safety profile toward the normal human cell line WI-38, with IC > 200 μM comparable to sorafenib (IC = 192 μM). In vitro enzymatic assays, 2h and 2l derivatives emerged as potent multi-kinase inhibitors targeting VEGFR-2, EGFR, and HER-2 with IC = 0.20, 0.21, and 0.19 μM, respectively, and IC = 0.67, 0.53, and 0.40 μM, respectively, hence circumventing cancer resistance mechanisms. The most potent Compound 2h prompted apoptosis and necrosis at % G0-G1 phase in HCT-116 via the activation of caspase-3 and 8, with significant downregulation of anti-apoptotic protein Bcl-2. Additionally, Compound 2h markedly suppressed immunomodulatory proteins TNF-α and IL-6 levels by 80.9% and 88.2%, respectively, in comparison to dexamethasone (82.7% and 93.2%, respectively), which attenuates tumor-promoting inflammation, disrupting pro-survival signaling pathways and metastasis. In silico ADMET, toxicity, and molecular docking studies were performed; notably, the docking simulations generated an interesting hypothesis for potential direct binding to Bcl-2, an effect distinct from the experimentally observed downstream downregulation of its expression. The present results pave the way for further developing of 2h candidate as a multi-tyrosine kinases inhibitor toward colon cancer cells.
Exploring the Role of Novel N (4) Substituted 5,7-Dibromoisatin Thiosemicarbazones in Modulating PTOV1 Activity for Therapeutic Relevance in Breast Cancer.
Kumar P, Chaudhary U, Mahiya K … +4 more , Chandra A, Goel VK, Pokharel YR, Yadav PN
Drug Dev Res · 2026 May · PMID 42108773 · Publisher ↗
We herein report the synthesis, and antiproliferative evaluation of a novel series of N(4)-substituted 5,7-dibromoisatin thiosemicarbazones (TSCs). Structure and activity based approach was used to synthesize derivatives...
We herein report the synthesis, and antiproliferative evaluation of a novel series of N(4)-substituted 5,7-dibromoisatin thiosemicarbazones (TSCs). Structure and activity based approach was used to synthesize derivatives: N(4)-pyrrolidinyl (L1), N(4)-piperidinyl (L2), N(4)-morpholinyl (L3), N(4)-methyl (L4), and N(4)-ethyl (L5). The compounds were characterized by elemental analysis, FTIR, H NMR, C NMR, UV-Vis spectroscopy, HRMS and single crystal X-ray analysis. The antiproliferative activity of the synthesized TSCs was evaluated in a dose-dependent manner against breast (MCF-7, MDA-MB-231), skin (A431), lung (A549, NCI-H460), and prostate (PC3) cancer cell lines. L3 and L5 exhibited enhanced cytotoxicity in the low micromolar range of IC; 1.16-2.47 µM. Notably, L5 showed superior potency in MCF-7 cells with IC; 1.16 µM compared to the FDA-approved thiosemicarbazone Triapine with IC; 4.27 µM, while displaying minimal toxicity toward non-tumorigenic MCF-10a breast epithelial cells with selectivity index > 86.20, consistent with ADMET predictions. Molecular docking and molecular dynamics simulations demonstrated stronger binding affinity and greater complex stability of L5 with PTOV1 compared to the FDA approved drug Lenalidomide, supporting L5 drug likeness and therapeutic potential. Mechanistic investigations through functional assays like crystal violet assays, flow cytometry, immunoblotting, and microscopy revealed that L5 induces G0/G1 cell-cycle arrest, suppresses cell migration, invasion, colony formation, 3D spheroid growth, and promotes apoptotic cell death in MCF-7. Western blot analysis provided direct mechanistic evidence that L5 downregulates PTOV1 expression, leading to reduced phosphorylation of AKT1/2/3 and c-Jun, reduced β-catenin nuclear translocation, and decreased MMP-2 expression. L5 enhanced H2AX phosphorylation, suppressed PARP and BCL-XL levels, and increased active caspase-3 driving L5 induced apoptosis. This study identifies L5 as a potent anticancer agent in breast cancer, acting through modulation of the PTOV1-AKT-β-catenin signaling axis, and highlights PTOV1 as a promising therapeutic target.
Structure-Guided Design and Mechanistic Elucidation of New Chromene Derivatives as Selective Vascular Endothelial Growth Factor Receptor-2 Inhibitors With Potent Anticancer Activity.
Elkady H, Elgammal WE, Eissa IH … +6 more , Mahdy HA, Alsfouk AA, Amin FG, Husein DZ, Metwaly AM, Elkaeed EB
Drug Dev Res · 2026 May · PMID 42070106 · Publisher ↗
In this study, a novel series of chromene-based derivatives was rationally designed as potential VEGFR-2 inhibitors based on key structural and pharmacophoric features required for antiangiogenic activity. Accordingly, t...
In this study, a novel series of chromene-based derivatives was rationally designed as potential VEGFR-2 inhibitors based on key structural and pharmacophoric features required for antiangiogenic activity. Accordingly, twelve chromene derivatives (13a-e, 15a-e, and 17a-b) were successfully synthesized and structurally characterized. The synthesized compounds were evaluated in vitro for their cytotoxic activity against human cancer cell lines (MCF-7, HepG-2, and HCT-116), in addition to normal WI-38 and WISH cells. Among the tested compounds, compound 13a demonstrated the most potent and selective antiproliferative activity, exhibiting low micromolar IC values and favorable selectivity indices. Enzymatic assays confirmed its VEGFR-2 inhibitory activity (IC = 1.666 ± 0.025 µM), comparable to the reference drug sorafenib. Mechanistic investigations revealed that compound 13a effectively inhibited cancer cell migration in a wound healing assay, highlighting its potential antiangiogenic properties. Furthermore, compound 13a induced significant G0/G1 cell cycle arrest in MCF-7 cells and triggered apoptosis, as evidenced by Annexin V/PI staining. To support the experimental findings, Density Functional Theory (DFT) calculations confirmed favorable structural stability and electronic properties. Molecular docking studies demonstrated strong binding interactions within the VEGFR-2 ATP-binding site. These results were further validated by 200 ns molecular dynamics simulations, MM-GBSA binding free energy calculations, Protein-Ligand Interaction Fingerprints (Pro-LIF), Principal Component Analysis of Trajectories (PCA-T), and Free Energy Landscape (FEL) analyses, confirming the dynamic stability and favorable energetics of the VEGFR-2-13a complex. Overall, this integrated experimental and computational study identifies compound 13a as a promising VEGFR-2-targeted anticancer lead warranting further preclinical investigation.
Antitumor Activity of Sodium Selenite, Palbociclib, and Disulfiram Against Osteosarcoma and Rhabdomyosarcoma Cell Lines.
Chico MÁ, Doello K, Ortiz R … +4 more , Peña M, Melguizo C, Mesas C, Prados J
Drug Dev Res · 2026 May · PMID 42070104 · Full text
Osteosarcoma and rhabdomyosarcoma are the most common pediatric sarcomas, yet prognosis remains poor due to high relapse rates. This study investigates the repurposing of palbociclib (PB) and disulfiram (DS), alongside s...
Osteosarcoma and rhabdomyosarcoma are the most common pediatric sarcomas, yet prognosis remains poor due to high relapse rates. This study investigates the repurposing of palbociclib (PB) and disulfiram (DS), alongside sodium selenite (SS), as potential therapeutic strategies. Using cell lines, we assessed antiproliferative effects via Sulforhodamine B, colony formation, and wound healing assays. Mechanisms of action were explored through protein expression of PARP-1 (apoptosis) and LC3β (autophagy), qPCR for stem cell markers, and ROS quantification. Finally, antitumor and anti-angiogenic efficacy was validated using the in ovo chicken chorioallantoic membrane (CAM) assay. Results demonstrated that all three compounds inhibited proliferation, migration, and spheroid growth while inducing apoptosis and autophagy. Notably, SS and PB elevated ROS levels, triggering parthanatos-mediated cell death via AIF nuclear translocation. SS also exhibited significant anti-angiogenic activity. Xenograft CAM models confirmed the in vivo efficacy of SS, PB, and DS against RD and MG63 cells. These findings suggest that SS, PB, and DS are promising candidates for pediatric sarcoma treatment, particularly as maintenance therapies to prevent relapse following conventional radical treatment.
Design, Synthesis, Biological Evaluation, and Molecular Modeling Studies of Novel 2-Aminothiazole Derivatives as Potential FOXM1 Inhibitors for Triple-Negative Breast Cancer Therapy and Structure-Activity Relationship.
Abusharkh KAN, Çınar V, Onder A … +6 more , Sıkık M, Mustafa Guzel, Hamurcu Z, Ozpolat B, Ay M, Comert Onder F
Drug Dev Res · 2026 May · PMID 42070099 · Full text
Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical,...
Triple Negative Breast Cancer (TNBC) is one of the most aggressive subtypes of breast cancer (BC), which is associated with a very poor prognosis. It is a broad category of tumors with a variety of biological, clinical, and morphological characteristics. FOXM1 is a pivotal transcription factor that modulates proliferation-associated genes through complex protein-DNA and protein-protein interactions, making it a highly attractive target in cancer therapy. However, existing small-molecule inhibitors often suffer from limited specificity and efficacy. In this study, we designed, synthesized, and evaluated novel series of 2-aminothiazole derivatives (C1-C15) as potential FOXM1 inhibitors. Molecular docking and molecular dynamics (MD) simulations were employed to investigate the binding interactions of these compounds with the FOXM1 DNA-binding domain (FOXM1-DBD). Structural analysis highlighted the importance of crucial residues, including Asn283, His287, and Arg286, in mediating inhibitory activity. Among the synthesized compounds, C11 exhibited remarkable structural alignment and interaction patterns with FOXM1-DBD, comparable to the reference inhibitor FDI-6. In vitro studies using TNBC cell lines (MDA-MB-231, BT-549, and BT-20) demonstrated that compound C11 significantly outperformed FDI-6 in potency. Western blot analysis revealed that C11 effectively suppressed FOXM1 transcriptional activity at concentrations of 10 µM in BT-549 cells and 20 µM in MDA-MB-231 cells. These findings underscore the potential of C11 as a potent FOXM1 inhibitor and highlight its promise for further development in TNBC therapy.
Design, Green Synthesis, and Biological Evaluation of Novel Triaryl-Tethered Acryloyl Derivatives as New Generation β-Tubulin Inhibitors for Hepatocellular Carcinoma Treatment.
Al-Mutairi AA, Mourad MAE, Alqahtani AS … +2 more , Elmaaty AA, Zaki I
Drug Dev Res · 2026 May · PMID 42059208 · Publisher ↗
Inhibition of β-tubulin polymerization has been set as promising therapeutic strategy for cancer therapy. Accordingly, a new set of triaryl-tethered acetohydrazide-acryloyl derivatives were designed and synthesized. The...
Inhibition of β-tubulin polymerization has been set as promising therapeutic strategy for cancer therapy. Accordingly, a new set of triaryl-tethered acetohydrazide-acryloyl derivatives were designed and synthesized. The antiproliferative influence was evaluated against liver Huh-7 cell line using MTT colorimetric method with Doxorubicin as a positive control. Compounds 3b, 4f, 4i, and 4j showed excellent cytotoxic activity against Huh-7 cell line. Among the investigated compounds, 2-(naphthalene-2-yloxy)acetohydrazide having 2-(4-methyl)-3-(3,4,5-trimethoxybenzamido)acryloyl moiety (compound 4i) was the most active one with an IC value of 2.46 µM. In addition, all compounds were further evaluated in vitro for their β-tubulin polymerization inhibition activity. Results found that compound 4i showed high activity against β-tubulin polymerization with an IC value of 2.29 µM, surpassing the activity of the reference Podophyllotoxin (IC = 4.45 µM). Further studies revealed the ability of the promising compound 4i to induce apoptosis and halt the cellular cycle at G2/M phase. Furthermore, the apoptosis-inducing activity of naphthalene-tethered acryloyl moiety 4i was correlated to the downregulation of Bcl-2 as well as elevation of both Bax and caspase 9 as concluded from RT-PCR immunoassay measurements. Finally, molecular docking studies were also performed to explain the displayed inhibitory activities.
The Development of Chemical Probes for Targeting Coactivator Associated Arginine Methyltransferase 1 (CARM1) Inhibitors.
Rakesh KP, Verma SK, Singh MV … +4 more , Abuderman A, Verma S, Verma R, Soni S
Drug Dev Res · 2026 May · PMID 42053229 · Publisher ↗
As a transcriptional coactivator and associated arginine methyltransferase 1, CARM1 controls various biological functions. CARM1 was thought to be a prospective therapeutic target, as anomalous appearance of the gene has...
As a transcriptional coactivator and associated arginine methyltransferase 1, CARM1 controls various biological functions. CARM1 was thought to be a prospective therapeutic target, as anomalous appearance of the gene has been linked to the development of several cancer types. Since there aren't any CARM1 inhibitors available for use in clinical trials at the moment, Kindle is interested in the development of human pharmacological treatments that target CARM1. To confirm this PRMT as a therapeutic target, selective inhibitors of CARM1 would be helpful tools. In this review, we discuss the identification, description, and biological use of CARM1 inhibitors, focusing on significant developments in the field.
Sustained DNA Hypomethylation Induced by a DNA Methyltransferase 1 Inhibitor Triggers Apoptosis in Thyroid Cancer Cells.
Cheng CW, Fang WF, Wang YH … +2 more , Yang YM, Lin JD
Drug Dev Res · 2026 May · PMID 42048599 · Publisher ↗
DNA methylation, is catalyzed by DNA methyltransferases (DNMTs), and its aberrant patterns are implicated in thyroid cancer pathogenesis. The study aimed to investigate the association of DNMTs with thyroid cancer and ev...
DNA methylation, is catalyzed by DNA methyltransferases (DNMTs), and its aberrant patterns are implicated in thyroid cancer pathogenesis. The study aimed to investigate the association of DNMTs with thyroid cancer and evaluated the effects of sustained demethylating therapy in a cell-based study. DNMTs expressions in thyroid cancer were analyzed using GEO and TCGA datasets. Additionally, 16 paired and three unpaired papillary thyroid carcinoma (PTC) samples from Taipei Medical University (TMU), along with commercial tissue arrays, were analyzed. Furthermore, the effects of the covalent DNMT inhibitor, 5-azacytidine (5-Aza), and the DNMT1-selective inhibitor, GSK-3484862, on cell viability were evaluated in PTC and follicular thyroid carcinoma (FTC) cell lines. DNMT1 and DNMT3A were upregulated in PTC, with DNMT1 expression correlated with the BRAF mutation and lymph node invasion in TCGA data, findings further confirmed in the TMU cohort and tissue arrays. Short-term (24 h) 5-Aza treatment (1 and 5 µM) induced substantial cell death regardless of the DNA methylation status, whereas short-term GSK-3484862 (5 µM) treatment showed minimal cytotoxicity. In contrast, sustained low-dose GSK-3484862 treatment (approximately 1-3 weeks at 2 µM) effectively reduced global DNA methylation and decreased cell viability of TPC-1 and FTC-236 cells through apoptosis, rather than by inhibiting proliferation. In conclusion, DNMT1 overexpression in PTC suggests its involvement in thyroid carcinogenesis. Sustained inhibition of DNMT1 effectively reduced global DNA methylation and promoted apoptosis, highlighting the potential of prolonged DNMT1-targeted therapy. Further in vitro and in vivo studies are warranted to validate these results and elucidate the underlying mechanisms.
Discovery of Tetrahydropyrrolo[3,4-c]pyrrole-1,3-dione Derivatives as Novel RIPK1 Inhibitors via Pharmacophore-Based Virtual Screening.
Zeng X, Yu Y, Wu Y … +2 more , Chen G, Sheng R
Drug Dev Res · 2026 May · PMID 42043293 · Publisher ↗
RIPK1 regulates the pathways in programmed cell death, and is closely associated with inflammatory and immune diseases. Based on the pharmacophore-based virtual screening, compound 15, a tetrahydropyrrolo[3,4-c]pyrrole-1...
RIPK1 regulates the pathways in programmed cell death, and is closely associated with inflammatory and immune diseases. Based on the pharmacophore-based virtual screening, compound 15, a tetrahydropyrrolo[3,4-c]pyrrole-1,3-dione derivative, was identified as a hit of RIPK1 inhibitor with an IC value of 6.42 μM. Furthermore, a similarity searching was carried out to get more potent RIPK1 inhibitors. Among them, compound 21 showed obvious improvement in RIPK1 inhibitory activity with an IC value of 2.21 μM, accompanied with moderate anti-necroptosis activity in HT-29 cells (IC = 15.32 μM). Molecular dynamics (MD) simulations indicated that it probably functioned as a type III kinase inhibitor.
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