Biomolecules. 2025 Apr 11;15(4):565. doi: 10.3390/biom15040565.

ABSTRACT

Beta-hemoglobinopathies such as beta-thalassemia and sickle cell disease are severe genetic blood disorders affecting the beta globin chain of haemoglobin A (α2β2). Activation of delta globin, the non-alpha globin of HbA2 (α2δ2), could represent a possible approach to improve the clinical severity of these pathologies. Notably, the therapeutic potential of delta globin has been demonstrated in previous studies using a mouse model of beta-thalassemia and sickle cell disease. The present study evaluated delta globin gene activation by small molecules in erythroid cells isolated from transgenic murine foetal liver. A screening of 119 molecules, selected for their potential in drug repurposing, was performed without prior selection based on specific pathways of interest. Three candidates-Nexturastat, Stattic and Palbociclib-were found to have high efficacy on delta globin expression. Palbociclib also proved effective in increasing gamma globin expression. All of these compounds have pharmacokinetic profiles that are beneficial for clinical application, providing potential inducer agents of HbA2 that could have therapeutic effects in the treatment of beta-hemoglobinopathies.

PMID:40305292 | DOI:10.3390/biom15040565

Cell Biochem Biophys. 2025 Apr 30. doi: 10.1007/s12013-025-01762-x. Online ahead of print.

ABSTRACT

Acute Respiratory Distress Syndrome (ARDS) is a severe lung disease with a high fatality rate and few treatment options. Targeting certain signalling pathways, notably the Transforming Growth Factor-beta (TGF-beta) signalling pathway, has emerged as a promising option for ARDS therapy. We identified TGF-beta Receptor 1 (TGFBR1) as a major target for ARDS treatment using the STRING and KEGG databases and validated TGFBR1's critical function in the TGF-beta signalling pathway, which is important in ARDS pathogenesis. To find prospective TGFBR1 inhibitors, we selected two FDA-approved medicines, Galunisertib and Vactosertib, which are established pharmacological profiles in cancer and fibrotic illnesses. Furthermore, the SwissSimilarity platform's ligand-based virtual screening revealed structurally related drugs in the DrugBank and ChEMBL databases. Among these, seven candidates were selected for further consideration. Molecular docking experiments found that DB08387 and CHEMBL14297639 had the strongest affinity for TGFBR1, creating strong hydrogen bonds at key sites. These findings point to their potential as TGFBR1 inhibitors in ARDS treatment. The pharmacokinetic screening revealed that most of the chosen compounds had favourable ADME features, with CHEMBL14297639 standing out for its low gastrointestinal absorption and limited cytochrome P450 inhibition. This study demonstrates the possibility of targeting TGFBR1 with Galunisertib, Vactosertib, and other prospective ARDS treatments. The findings lay the groundwork for additional experimental validation and the development of innovative therapeutics aimed at reducing ARDS severity.

PMID:40304856 | DOI:10.1007/s12013-025-01762-x

Clin Transl Sci. 2025 May;18(5):e70237. doi: 10.1111/cts.70237.

ABSTRACT

Clinical trials with investigator sponsors at academic sites have increased, in part due to studies involving drug repurposing, the process of identifying new uses for existing drugs that are initially conducted in patients rather than healthy participants. In contrast to industry- or government-sponsored trials, investigator-sponsored clinical studies, also known as investigator-initiated trials, are typically conducted at one or several academic centers and are resource-limited by finances and patient numbers. These studies can serve as crucial pilot studies to inform the design of larger, more definitive clinical trials. Drawing from the experience of working with clinical researchers in academic settings, this tutorial presents guidelines for writing clinical protocols for resource-limited investigator-sponsored studies that meet international standards and optimize the detection of meaningful signals or outcomes that can lead to investigation in larger well-controlled trials.

PMID:40304394 | DOI:10.1111/cts.70237

Front Pharmacol. 2025 Apr 15;16:1546836. doi: 10.3389/fphar.2025.1546836. eCollection 2025.

ABSTRACT

Vitiligo is a chronic autoimmune condition characterized by the destruction of melanocytes, leading to patchy loss of skin depigmentation. Although its precise cause remains unclear, recent evidence suggests that metabolic disturbances, particularly oxidative stress and mitochondrial dysfunction, may play a significant role in the pathogenesis of the disease. Oxidative stress is thought to damage melanocytes and trigger inflammatory responses, culminating in melanocyte immune-mediate destruction. Additionally, patients with vitiligo often exhibit extra-cutaneous metabolic abnormalities such as abnormal glucose metabolism, dyslipidemia, high fasting plasma glucose levels, high blood pressure, out of range C-peptide and low biological antioxidant capacity, suggesting a potential link between metabolic impairment and vitiligo development. This implies that the loss of functional melanocytes mirrors a more general systemic targetable dysfunction. Notably, therapies targeting metabolic pathways, particularly those involving mitochondrial metabolism, such as the peroxisome proliferator-activated nuclear receptor γ (PPARγ) agonists, are currently being investigated as potential treatments for vitiligo. PPARγ activation restores mitochondrial membrane potential, mitochondrial DNA copy number and, consequently, ATP production. Moreover, PPARγ agonists counteract oxidative stress, reduce inflammation, inhibit apoptosis, and maintain fatty acid metabolism, in addition to the well-known capability to enhance insulin sensitivity. Additionally, increasing evidence of a strong relationship between metabolic alterations and vitiligo pathogenesis suggests a role for other approved anti-diabetic treatments, like metformin and fibrates, in vitiligo treatment. Taken together, these data support the use of approaches alternative to traditional immune-suppressive treatments for the treatment of vitiligo.

PMID:40303919 | PMC:PMC12037623 | DOI:10.3389/fphar.2025.1546836

J Neuroinflammation. 2025 Apr 29;22(1):125. doi: 10.1186/s12974-025-03455-x.

ABSTRACT

BACKGROUND: Epalrestat (EPS), an aldose reductase inhibitor, is used to alleviate peripheral nerve disorder of diabetic patients in clinical therapy. Even though EPS exerted effects in central nervous system diseases, the neuroprotection and underlying molecular mechanism in neurodegenerative diseases, especially Parkinson's disease (PD), remains obscure. Our study aimed to investigate the potential of EPS suppressed PD progression both in vivo and in vitro.

METHODS: We used 1-methyl-4-phenylpyridillium ion (MPP+)-treated PD cells and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mice to investigate the protective function and molecular mechanism of EPS in PD. EPS was administered three times daily through oral route 3 days before model establishment for 5 consecutive days. Behavioral manifestation of mice was conducted using open field test, rotarod test and CatWalk gait analysis. Immunofluorescence was used to detect dopaminergic (DAergic) neurons survival in the substantia nigra. Subsequently, oxidative stress, mitochondrial function and KEAP1/Nrf2 signaling pathway in PD models were detected through molecular biology methods to assess the effect and downstream mechanisms of EPS on PD. Molecular docking, surface plasmon resonance and cellular thermal shift assay were used to verify the direct binding of EPS and KEAP1.

RESULTS: We found that EPS exhibited potent antiparkinsonian activity in PD models both in vivo and in vitro. PD models treated with EPS manifested alleviated oxidative stress and mitochondrial dysfunction. Furthermore, we found EPS activated the Nrf2 signaling pathway which contributed to DAergic neurons survival in PD models. Particularly, we firstly confirmed that EPS competitively binds to KEAP1 and enhanced its degradation, thereby activating the Nrf2 signaling pathway.

CONCLUSIONS: Collectively, EPS attenuates oxidative stress and mitochondrial dysfunction by directly binding KEAP1 to activate the KEAP1/Nrf2 signaling pathway, further reducing DAergic neurons damage. These findings suggest that EPS has great potential to become a therapeutic for PD as a clinically effective and safe medicine.

PMID:40301912 | DOI:10.1186/s12974-025-03455-x

Biomed Pharmacother. 2025 Apr 28;187:118104. doi: 10.1016/j.biopha.2025.118104. Online ahead of print.

ABSTRACT

Dengue virus (DENV) threatens global health; specific antiviral drugs are required to combat it. Such anti-DENV therapeutics can be rapidly developed by repositioning the drugs approved for other indications. This study investigated six medications of different classes drawn from a library of molecules. In silico analyses were performed to determine potential binding affinity for the DENV non-structural protein NS3 protease and NS5 RNA-dependent RNA polymerase (RdRp). Of the six candidates, galidesivir and tadalafil showed the highest binding affinities for the DENV NS3 protease and NS5 RdRp, with tadalafil demonstrating the highest binding affinity. Galidesivir and tadalafil substantially suppressed viral replication in DENV replicon cells without inducing cytotoxicity and showed half-maximal inhibitory concentrations of 10 μM and 2.56 μM, respectively. Both galidesivir and tadalafil effectively suppress DENV infection in human hepatoma and baby hamster kidney cells, and tadalafil demonstrates protease-inhibitory activity. In an AG129 mouse model of DENV infection, both galidesivir and tadalafil reduced viral loads in the serum, with tadalafil producing a notable reduction by day four. Both drugs markedly suppressed DENV replication in the hepatic tissue. Histopathologically, both galidesivir- and tadalafil-treated mice showed alleviation of DENV-induced lesions in the spleen and liver, indicating the potential therapeutic effects of these drugs. These findings highlight the potential of repositioning galidesivir and tadalafil as effective anti-DENV therapies with low cytotoxicity, meeting the urgent global need for new therapeutic agents against this pathogen.

PMID:40300391 | DOI:10.1016/j.biopha.2025.118104

IEEE J Biomed Health Inform. 2025 Apr 29;PP. doi: 10.1109/JBHI.2025.3565721. Online ahead of print.

ABSTRACT

As an effective and low-risk approach to identify new therapeutic pathways for existing drugs, drug repositioning has been extensively utilized to expedit drug discovery processes. However, current knowledge graph (KG)-based methodologies encounter several hurdles in this context. Firstly, most graph neural network (GNN)- based approaches fail to adequately capture the intricate relationships between drug-drug, drug-disease, or diseasedisease. Secondly, the subtle synergistic mechanisms between drugs and diseases remain underexplored. Lastly, the training of knowledge graph embedding (KGE) methods is susceptible to noise, leading to unstable model optimization. To address these challenges, we intruduce KRANE, a knowledge-driven and relation-aware synergistic learning method for drug repositioning. KRANE addresses these issues through three innovative modules. Firstly, we design a relation-aware feature extractor (RAFE), which utilizes the contextual triples attention scores in KG to effectively integrate drug-related knowledge and enhance the representation of complex relational features. Secondly, we adopt a synergistic feature reconstruction module as a decoder to extract synergistic heterogeneous feature interactions between drugs and diseases from entity and relation representations. Finally, we propose a knowledgeregulated loss function to mitigate the impact of noise on model training. Experiments conducted on three publicly available datasets demonstrate that KRANE significantly outperforms existing methods. The source code and datasets are available at https://github.com/qifen37/KRANE.

PMID:40299742 | DOI:10.1109/JBHI.2025.3565721

Pac Symp Biocomput. 2025;30:441-456. doi: 10.1142/9789819807024_0032.

ABSTRACT

Given the complexity and multifactorial nature of Alzheimer's disease, investigating potential drug-gene targets is imperative for developing effective therapies and advancing our understanding of the underlying mechanisms driving the disease. We present an explainable ML model that integrates the role and impact of gene interactions to drive the genomic variant feature selection. The model leverages both the Alzheimer's knowledge base and the Drug-Gene interaction database (DGIdb) to identify a list of biologically plausible novel gene-drug targets for further investigation. Model validation is performed on an ethnically diverse study sample obtained from the Alzheimer's Disease Sequencing Project (ADSP), a multi-ancestry multi-cohort genomic study. To mitigate population stratification and spurious associations from ML analysis, we implemented novel data curation methods. The study outcomes include a set of possible gene targets for further functional follow-up and drug repurposing.

PMID:40299608 | DOI:10.1142/9789819807024_0032

Biomedicines. 2025 Mar 31;13(4):839. doi: 10.3390/biomedicines13040839.

ABSTRACT

Background: Although mTOR has long been regarded as a promising target for cancer treatment, the efficacy of mTOR inhibitors in most clinical trials has been rather limited. Nevertheless, their favorable safety profile has opened up opportunities for drug repurposing, even as their potential applications across various diseases remain largely unexplored. Methods: We performed an MR-PheWAS analysis across 1431 phenotypes to explore drug repurposing opportunities. We analyzed GWAS data of 452 plasma metabolites, 731 immune traits, and 412 gut microbiota to uncover potential mechanisms for the causal link between the mTOR gene and body mass index (BMI). Results: A causal link between mTOR gene expression and BMI has been established. Additionally, mTOR-related vulnerabilities associated with BMI, including alterations in metabolites, immune traits, and gut microbiota, were identified. Conclusions: The identified causal relationship between mTOR and BMI suggests novel potential non-cancer applications for mTOR inhibitors.

PMID:40299431 | DOI:10.3390/biomedicines13040839

J Proteome Res. 2025 Apr 29. doi: 10.1021/acs.jproteome.4c00885. Online ahead of print.

ABSTRACT

Cisplatin-based chemotherapy is a cornerstone in treating cervical cancer, yet the efficacy is frequently limited by the rapid onset of drug resistance, a major challenge in clinical management. To investigate this, we employed HPV16+ human cervix squamous carcinoma cells, SiHa (CIS/S), and their cisplatin-resistant subline (CIS/R) as a model. Using DIA-based proteomics, we identified 5152 protein groups and over 50,000 peptides with a global FDR <1%. Comparative analysis revealed 123 differentially expressed proteins. Gene Set Enrichment Analysis (GSEA) highlighted proteins involved in DNA damage, metabolism, and repair pathways (RFC4, RFC3, RFC2, DUT, DDX54, CDCA8, CDK7, CHAF1B, and GTF2F1), suggesting a role in developing acquired cisplatin resistance. Pathways related to mitotic spindle assembly and P53 signaling were found to be perturbed in resistant cells. Next, we screened a library of approx. 240 FDA-approved drugs against three protein targets and found four small-molecular ligands as potential hits for further in vitro validation. Cabozantinib and sorafenib gave us positive results in terms of increasing the cisplatin sensitivity of CIS/R cells. In conclusion, our findings provide insights into the molecular mechanisms underpinning cisplatin resistance in cervical cancer and propose novel strategies for combating this resistance through targeted therapies and drug repurposing.

PMID:40298920 | DOI:10.1021/acs.jproteome.4c00885

Antioxidants (Basel). 2025 Mar 27;14(4):396. doi: 10.3390/antiox14040396.

ABSTRACT

BACKGROUND: All the processes leading to neurodegeneration cannot be addressed with just one medication. Combinations of drugs affecting various disease mechanisms concurrently could demonstrate improved effect in slowing the course of Parkinson's disease (PD).

OBJECTIVE: This was a drug-repurposing experiment designed to assess several combinations of nine drugs for possible added or synergistic efficacy using in vitro models of PD.

METHODS: We evaluated 44 combinations of the nine medications (sodium phenylbutyrate, terazosin, exenatide, ambroxol, deferiprone, coenzyme-Q10, creatine, dasatinib and tauroursodeoxycholic acid) selected for their previously demonstrated evidence of their impact on different targets, showing neuroprotective properties in preclinical models of PD. We utilized wild-type induced pluripotent stem-cell-derived human dopaminergic neurons treated with 1-methyl-4-phenylpyridinium for initial screening. We retested some combinations using an idiopathic PD patient-derived induced pluripotent stem cell line and alpha-synuclein triplication line. We assessed anti-neuroinflammatory effects using human microglia cells. As metrics, we evaluated neurite length, number of branch points per mm2, the number of live neurons, neurofilament heavy chain and pro-inflammatory cytokines.

RESULTS: We have identified four combinations of two to three drugs that showed an additive protective effect in some endpoints. Only the combination of sodium phenylbutyrate, exenatide and tauroursodeoxycholic acid showed improvement in four endpoints studied.

CONCLUSIONS: We demonstrated that some of the medications, used in combination, can exert an additive neuroprotective effect in preclinical models of PD that is superior to that of each of the compounds individually. This project can lead to the development of the first treatment for PD that can slow or prevent its progression.

PMID:40298667 | DOI:10.3390/antiox14040396

Antibiotics (Basel). 2025 Apr 14;14(4):402. doi: 10.3390/antibiotics14040402.

ABSTRACT

Background/Objectives: Antibiotic therapy faces challenges from rising acquired and biofilm-related antibiotic resistance rates. High resistance levels to commonly used antibiotics have been observed in methicillin-resistant Staphylococcus aureus (MRSA) strains among cystic fibrosis (CF) patients, indicating an urgent need for new antibacterial agents. This study aimed to identify potential novel therapeutics with antibacterial and antibiofilm activities against an MRSA CF strain by screening, for the first time, the Drug Repurposing Compound Library (MedChem Express). Methods/Results: Among the 3386 compounds, a high-throughput screening-based spectrophotometric approach identified 2439 (72%), 654 (19.3%), and 426 (12.6%) drugs active against planktonic cells, biofilm formation, and preformed biofilm, respectively, although to different extents. The most active hits were 193 (5.7%), against planktonic cells, causing a 100% growth inhibition; 5 (0.14%), with excellent activity against biofilm formation (i.e., reduction ≥ 90%); and 4, showing high activity (i.e., 60% ≤ biofilm reduction < 90%) against preformed biofilms. The potential hits belonged to several primary research areas, with "cancer" being the most prevalent. After performing a literature review to identify other, already published biological properties that could be relevant to the CF lung environment (i.e., activity against other CF pathogens, and anti-inflammatory and anti-virulence potential), the most interesting hits were the following: 5-(N,N-Hexamethylene)-amiloride (diuretic), Toremifene (anticancer), Zafirlukast (antiasthmatic), Fenretide (anticancer), and Montelukast (antiasthmatic) against planktonic S. aureus cells; Hemin against biofilm formation; and Heparin, Clemastine (antihistaminic), and Bromfenac (nonsteroidal anti-inflammatory) against established biofilms. Conclusions: These findings warrant further in vitro and in vivo studies to confirm the potential of repurposing these compounds for managing lung infections caused by S. aureus in CF patients.

PMID:40298549 | DOI:10.3390/antibiotics14040402

Hum Mol Genet. 2025 Apr 29:ddaf061. doi: 10.1093/hmg/ddaf061. Online ahead of print.

ABSTRACT

The copper ionophore disulfiram (DSF) is commonly used to treat chronic alcoholism and has potential anti-cancer activity. Using a yeast-based screening assay of FDA-approved compounds, DSF was herein identified for its ability to improve oxidative phosphorylation-dependent growth of various yeast models of mitochondrial diseases caused by a wide range of defects in ATP synthase, complexes III and IV, cardiolipin remodeling, maintenance and translation of the mitochondrial genome. This compound also showed beneficial effects in cells derived from patients suffering from Barth or MELAS syndromes, two mitochondrial diseases associated respectively with a lack in cardiolipin remodeling and protein synthesis inside the organelle. We provide evidence that the rescuing activity of DSF results from its ability to transport copper ions across biological membranes. Indeed, other copper ionophores (pyrithione and elesclomol) and supplementation of the growth media with copper ions had also beneficial effects in yeast and human cells with dysfunctional mitochondria. Our data suggest that the copper-dependent rescuing activity in these cells results from a better capacity to assemble cytochrome c oxidase. Altogether, our findings hold promise for the development of new therapeutic strategies for mitochondrial disorders.

PMID:40298238 | DOI:10.1093/hmg/ddaf061

medRxiv [Preprint]. 2025 Apr 8:2025.04.07.25325038. doi: 10.1101/2025.04.07.25325038.

ABSTRACT

The urgent need for safe and effective therapies for Alzheimer's disease (AD) has spurred a growing interest in repurposing existing drugs to treat or prevent AD. In this study, we combined multi-omics and clinical data to investigate possible repurposing opportunities for AD. We performed transcriptome-wide association studies (TWAS) to construct gene expression signatures of AD from publicly available GWAS summary statistics, using both transcriptome prediction models for 49 tissues from the Genotype-Tissue Expression (GTEx) project and microglia-specific models trained on eQTL data from the Microglia Genomic Atlas (MiGA). We then identified compounds capable of reversing the AD-associated changes in gene expression observed in these signatures by querying the Connectivity Map (CMap) drug perturbation database. Out of >2,000 small-molecule compounds in CMap, aspirin emerged as the most promising AD repurposing candidate. To investigate the longitudinal effects of aspirin use on AD, we collected drug exposure and AD coded diagnoses from three independent sources of real-world data: electronic health records (EHRs) from Vanderbilt University Medical Center (VUMC) and the National Institutes of Health All of Us Research Program, along with national healthcare claims from the MarketScan Research Databases. In meta-analysis of EHR data from VUMC and All of Us , we found that aspirin use before age 65 was associated with decreased risk of incident AD (hazard ratio=0.76, 95% confidence interval [CI]: 0.64-0.89, P =0.001). Consistent with the findings utilizing EHR data, analysis of claims data from MarketScan revealed significantly lower odds of aspirin exposure among AD cases compared to matched controls (odds ratio=0.32, 95% CI: 0.28-0.38, P <0.001). Our results demonstrate the value of integrating genetic and clinical data for drug repurposing studies and highlight aspirin as a promising repurposing candidate for AD, warranting further investigation in clinical trials.

PMID:40297415 | PMC:PMC12036415 | DOI:10.1101/2025.04.07.25325038

Anticancer Res. 2025 May;45(5):1981-1995. doi: 10.21873/anticanres.17574.

ABSTRACT

BACKGROUND/AIM: SH003, a novel herbal mixture consisting of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, has shown promising anti-cancer effects in various cancers, including non-small cell lung cancer (NSCLC), which comprises approximately 85% of all lung cancer cases. Characterized by high mortality rates due to late-stage diagnosis and frequent development of resistance to traditional therapies, NSCLC is a significant clinical challenge. This study investigated the anti-cancer effects of SH003 on NSCLC cells, focusing on its role in modulating receptor tyrosine kinase (RTK) signaling pathways.

MATERIALS AND METHODS: NSCLC cell lines (A549, H460, HCC827) were treated with SH003 to evaluate cell viability (MTT assay), colony formation, apoptosis (Annexin V/7-AAD staining, western blot), and cell cycle distribution (PI staining). Phosphorylation of RTKs and related signaling molecules was analyzed using a phospho-RTK array and western blot. In vivo anti-tumor effects were assessed using an A549 xenograft mouse model treated orally with SH003.

RESULTS: NSCLC cell lines A549, H460, and HCC827 treated with SH003 showed significant, dose-dependent cell viability and colony formation reductions. SH003 induced apoptosis, evidenced by increased cleaved PARP and caspase-8 levels, and caused G1/S cell cycle arrest. Additionally, SH003 treatment decreased phosphorylation of multiple receptor tyrosine kinases (RTKs), including ErbB4, FGFR1, FGFR3, and PDGFRβ, as confirmed by an RTK array. In an A549 xenograft mouse model, SH003 inhibited tumor growth without affecting body weight, indicating low systemic toxicity.

CONCLUSION: SH003 is a promising multi-target therapeutic agent for NSCLC, offering a novel strategy to improve patient outcomes.

PMID:40295074 | DOI:10.21873/anticanres.17574

Anticancer Res. 2025 May;45(5):1965-1980. doi: 10.21873/anticanres.17573.

ABSTRACT

BACKGROUND/AIM: Colon cancer is the most prevalent type of gastrointestinal cancer, characterized by high incidence and mortality rates despite advancements in diagnosis and treatment. Although chemotherapy is the standard treatment for advanced cases, survival benefits are often limited, highlighting the need for innovative therapeutic strategies. SH003, an herbal mixture composed of Astragalus membranaceus, Angelica gigas, and Trichosanthes kirilowii Maximowicz, has demonstrated anticancer properties across various cancer types. This study aimed to explore the anticancer effects of SH003 on colon cancer through in vitro and in vivo experiments.

MATERIALS AND METHODS: In vitro studies were conducted using human colon cancer cell lines, including HCT116, HT29, SW480, SW620, LoVo, LS174T, H508, and LS1034. Cell viability assays were performed to determine IC50 values over time. Apoptosis induction was assessed through Western blot analysis. Cell cycle progression was analyzed by examining the expression of cell cycle-related proteins. The disruption of the RTK-STAT3 signaling pathway was evaluated by measuring the phosphorylation of ALK using RTK-array. In vivo experiments involved establishing an HCT116 xenograft mouse model to assess tumor growth inhibition and systemic toxicity following SH003 administration.

RESULTS: SH003 significantly reduced cell viability in all tested colon cancer cell lines, with IC50 values decreasing over time, indicating a time-dependent cytotoxic effect. Apoptosis induction was confirmed by increased levels of cleaved PARP, caspase-3, caspase-8, and caspase-9. SH003 also induced G1/S phase cell cycle arrest, as evidenced by decreased expression of p-Rb, CDK2, CDK4, and Cyclin D1. Furthermore, SH003 disrupted the RTK-STAT3 signaling pathway by reducing ALK phosphorylation and decreasing the levels of p-STAT3, c-Myc, and cyclin D1. In vivo, SH003 significantly suppressed tumor growth in the HCT116 xenograft mouse model, reducing tumor volumes without causing notable systemic toxicity.

CONCLUSION: These findings suggest that SH003 possesses robust anticancer effects against colon cancer by inducing apoptosis, causing cell cycle arrest, and disrupting RTK-STAT3 signaling. The in vivo results further confirm SH003's efficacy and safety, supporting its potential as a promising therapeutic option for colon cancer treatment. Further studies are warranted to elucidate its mechanisms and clinical applicability.

PMID:40295067 | DOI:10.21873/anticanres.17573

In Silico Pharmacol. 2025 Apr 24;13(2):70. doi: 10.1007/s40203-025-00355-z. eCollection 2025.

ABSTRACT

Marburg Virus (MARV) presents a significant threat to human health, highlighting the urgent need for effective therapeutics. The MARV genome encodes a multifunctional 'large' L protein that plays a crucial role in polymerase, capping, and methyltransferase activities. Within this protein, the 2'-O-methyltransferase (2'-O-MTase) domain is essential for viral replication and immune evasion, making it a promising therapeutic target. However, the lack of structural data on this domain limits drug discovery efforts. To address this challenge, we utilized AlphaFold2 to predict a 3D structure of the MARV 2'-O-MTase domain. Molecular docking with its natural ligand, S-adenosyl methionine (SAM), allowed us to identify key active-site residues involved in ligand binding. We then screened 62 known inhibitors against this domain and identified four promising candidates: Lifirafenib (- 9.5 kcal/mol), Dolutegravir (- 8.5 kcal/mol), BRD3969 (- 8.3 kcal/mol), and JFD00244 (- 8.2 kcal/mol). Further, we assessed the pharmacokinetic and pharmacodynamic properties of these compounds to evaluate their drug-likeness. Molecular dynamics simulations, along with MM/GBSA free energy calculations, confirmed stable interactions between the selected inhibitors and the target domain. While these findings highlight promising candidates for MARV, experimental validation through in vitro and in vivo assays is essential to assess their safety and efficacy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-025-00355-z.

PMID:40291443 | PMC:PMC12018677 | DOI:10.1007/s40203-025-00355-z

ACS Omega. 2025 Feb 22;10(15):14980-14993. doi: 10.1021/acsomega.4c10338. eCollection 2025 Apr 22.

ABSTRACT

Huntington's disease (HD) and Spinocerebellar Ataxia (SCA) are debilitating neurological disorders triggered by the expansion of CAG sequences within the specific genes (HTT and ATXN, respectively). These are characterized as poly glutamine (polyQ) disorders, which are marked by widespread neurodegeneration and metabolic irregularities across systemic, cellular, and intracellular levels. This study aimed to identify small molecules that specifically interact with and target the toxic CAG repeat RNA. Here, we investigated the neuroprotective effects of Oseltamivir, an antiviral drug, against the HD and SCA-causing CAG repeats, through biophysical, cellular, and Drosophila model-based studies. Using a multidimensional approach encompassing biophysical techniques, cellular assays, and a Drosophila model, we explored Oseltamivir's interaction with toxic CAG repeat RNA. Our comprehensive analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), electrophoretic mobility shift assay (EMSA), and nuclear magnetic resonance (NMR) spectroscopy, demonstrated Oseltamivir's specific binding affinity for AA mismatches and its potential to mitigate the toxicity associated with polyQ aggregation. Moreover, the identified U.S. FDA-approved drug effectively mitigated polyQ-induced toxicity in both HD cells and the Drosophila model of the disease. The results obtained from this drug repurposing approach are indicative of the neuro-shielding role of Oseltamivir in HD and several SCAs, paving the way for its translation into clinical practice to benefit patients afflicted with these devastating diseases.

PMID:40290909 | PMC:PMC12019426 | DOI:10.1021/acsomega.4c10338

EClinicalMedicine. 2025 Mar 25;82:103102. doi: 10.1016/j.eclinm.2025.103102. eCollection 2025 Apr.

ABSTRACT

The kidney disease: Improving Global Outcomes (KDIGO) guideline recommends assessing kidney function using glomerular filtration rate (GFR) either through direct measurement or through estimation (eGFR) and describes a standardised classification of reduced kidney function. KDIGO guidelines have been adopted by most internal medicine specialities for the assessment and classification of kidney function, but not by cancer medicine. The development of the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) aims to overcome the perceived challenges with KDIGO recommendations by describing their utility in patients with cancer. Two virtual, consensus building workshops were held consecutively, involving international, multidisciplinary participants (Part 1 of ADDIKD development). During these workshops, three consensus recommendations were agreed upon based on KDIGO's principles; to standardise kidney function assessment, classify kidney function, and determine a uniform approach to dose anticancer drugs in patients with reduced kidney function. Cancer clinicians attending the workshops identified issues regarding the adoption of KDIGO's recommendations. These issues were addressed by nephrologists, clinical pharmacologists, and other clinicians with extensive experience in the contemporary assessment of kidney function. The key concern for cancer specialists was a hesitancy to move away from the familiar and long-standing practice of using the Cockcroft-Gault equation to estimate creatinine clearance. The consensus building within the two multidisciplinary workshops allowed a thorough assessment of the evidence and clarified how directly measured GFR and eGFR, rather than creatinine clearance, could be optimally utilised in cancer care. The development of Part 1 of the ADDIKD guideline represents a standardised, contemporary approach to the assessment, classification, and utility of kidney function in the setting of cancer care and it harmonises with the approach used in other areas of medicine internationally.

FUNDING: Development of the ADDIKD guideline is funded by the Cancer Institute NSW as part of the NSW Government and received no funding from external commercial sources.

PMID:40290845 | PMC:PMC12034077 | DOI:10.1016/j.eclinm.2025.103102

EClinicalMedicine. 2025 Mar 25;82:103161. doi: 10.1016/j.eclinm.2025.103161. eCollection 2025 Apr.

ABSTRACT

Part 2 of the International Consensus Guideline on Anticancer Drug Dosing in Kidney Dysfunction (ADDIKD) offers drug-specific consensus recommendations based on both evidence and practical experience. These recommendations build upon the kidney function assessment and classification guidelines established in Part 1 of ADDIKD. Here we illustrate how dosing recommendations differ between ADDIKD and existing guidance for four commonly used drugs: methotrexate, cisplatin, carboplatin and nivolumab. We then describe how the recommendations can be distilled into practice points for methotrexate and cisplatin. While ADDIKD is a significant improvement from previous guidelines, adoption of this new guideline requires further endorsement from key external stakeholders, 'change championing' by clinicians locally and encouraging its integration into existing reference sources, clinical trial protocols and electronic prescribing systems.

FUNDING: Development of the ADDIKD guideline is funded by the NSW Government as part of the Cancer Institute NSW and received no funding from external commercial sources.

PMID:40290844 | PMC:PMC12034076 | DOI:10.1016/j.eclinm.2025.103161