Search Results (307)

Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed disease face poor long-term survival odds. Topoisomerase 1 (TOP1) inhibitors are commonly used therapeutics in ES relapse regimens. Methods: In this work, we used a genome-wide CRISPR knockout library screen to identify the deletion of the TOP1 gene as a mechanism for resistance to topoisomerase 1 inhibitors. Using isogenic cell line models, we performed a high-throughput small-molecule screen to discover a small molecule, GNF-7, which had an IC50 that was 10-fold lower in TOP1-deficient cells when compared to the wild-type cells. Results: The characterization of GNF-7 demonstrated the molecule was highly active in the inhibition of CSK, p38α, EphA2, Lyn, and ZAK and specifically downregulated genes induced by the EWS::FLI1 fusion oncoprotein. Conclusions: Together, these results suggest that GNF-7 or small molecules with a similar kinase profile could be effective treatments for ES patients in combination with TOP1 inhibitors or for those patients who have developed resistance to TOP1 inhibitors. Full article

Antibody–drug conjugates (ADCs) have revolutionized precision oncology by enabling targeted drug delivery with improved therapeutic indices. Among these, deruxtecan (DXd)-based ADCs have demonstrated remarkable efficacy across a range of cancers, particularly in tumors expressing human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), and trophoblast cell surface antigen 2 (TROP2), including breast, lung, gastric, and other solid tumors. DXd, a potent topoisomerase I inhibitor, enhances the cytotoxic potential of ADCs through a cleavable and stable linker and a high drug-to-antibody ratio that ensures optimal drug release. The clinical success of trastuzumab DXd (Enhertu^®) and datopotamab DXd (Datroway^®), along with the ongoing development of patritumab DXd, has expanded the therapeutic potential of ADCs. However, challenges remain, including toxicity, resistance, and manufacturing scalability. This review discusses the mechanisms of action, clinical progress, and challenges of DXd-based ADCs, highlighting their transformative role in modern oncology and exploring future directions to optimize their efficacy and accessibility. Full article

Human topoisomerase III beta (hTOP3B) is a unique and important enzyme in human cells that plays a role in maintaining genome stability, affecting cellular aging, and potentially impacting viral replication. Its dual activity on both DNA and RNA makes it a valuable target for therapeutic interventions. hTOP3B has been shown to be required for the efficient replication of certain positive-sense ssRNA viruses including Dengue. We performed in silico screening of a library comprising drugs that are FDA-approved or undergoing clinical trials as potential drugs to identify potential inhibitors of hTOP3B. The topoisomerase activity assay of the identified virtual hits showed that bemcentinib, a compound known to target the AXL receptor tyrosine kinase, can inhibit hTOP3B relaxation activity. This is the first small molecule shown to inhibit the complete catalytic cycle of hTOP3B for the potential interference of the function of hTOP3B in antiviral application. Additional small molecules that share the N⁵,N³-1H-1,2,4-triazole-3,5-diamine moiety of bemcentinib were synthesized and tested for the inhibition of hTOP3B relaxation activity. Five compounds with comparable IC₅₀ to that of bemcentinib for the inhibition of hTOP3B were identified. These results suggest that the exploration of tyrosine kinase inhibitors and their analogs may allow the identification of novel potential topoisomerase inhibitors. Full article

A quinoline unit is present in many natural products and is an attractive pharmacophore for the development of clinical drugs, including antineoplastics. The title compound (QN) was synthesized via the condensation reaction between quinoline-2-carboxaldehyde and 2-nitrobenzhydrazide. QN’s structure was examined by X-ray diffraction and features extensive stacking interactions in the crystal. The compound is weakly toxic to HepG2 cells, with an IC₅₀ exceeding 400 μM for 48 h exposure. QN at 50 μM, with the dose reduction index in the range of 1.9–4.4, potentiated the cytotoxicity of several clinical chemotherapeutic drugs, including doxorubicin and other topoisomerase inhibitors, vincristine, and carboplatin, but not cisplatin or 5-fluorouracil. The calculated ADME parameters predict satisfactory drug-like properties for QN. Full article

Cancer remains one of the leading causes of morbidity and mortality worldwide, driving the search for innovative and selective therapeutic agents. Topoisomerases I and II are essential enzymes involved in key cellular processes such as DNA replication and transcription. They have emerged as valuable anticancer targets; thus, many inhibitors of topoisomerases have been designed and some of them are considered to be major anticancer agents such as anthracyclines, etoposide or irinotecan. A great deal of attention is currently being paid to chalcones, a class of naturally occurring compounds, since they exhibit a wide range of biological activities, including anticancer properties. These compounds are characterized by an open-chain structure and an α,β-unsaturated carbonyl moiety that enables interaction with cellular targets. Recent studies aiming to design anti-topoisomerase agents have identified both natural and synthetic chalcones, including chalcone-based hybrids. This review highlights the structural diversity of chalcones as topoisomerase inhibitors and particular attention is given to structure–activity relationship studies and molecular hybridization strategies aimed at optimizing the pharmacological profile of chalcones. These findings underline the potential of chalcones as promising scaffolds in the design of next-generation anticancer agents. Full article

Small cell lung cancer (SCLC) remains a challenge prognostically. A clinically silent early stage and predilection for early metastasis leads to over half of patients presenting with metastatic disease at the time of diagnosis. Akin to many other cancers, once SCLC metastasizes, current therapies begin to lose their effectiveness. The future of SCLC rests in innovative treatments aimed at improving patient outcomes. Chemotherapy and radiation remain the backbone treatment for SCLC. Most patients diagnosed with SCLC begin treatment with combination chemotherapy consisting of a platinum analog and topoisomerase inhibitor with or without concurrent radiation. Disease progression or recurrence warrants new treatment approaches. New chemotherapy combinations and advances in radiation precision offer patients novel approaches using the same backbone of treatment used in many other cancers. The introduction of newer therapeutic approaches, such as immune checkpoint inhibitors, small molecule targeted therapies, bispecific antibodies, and antibody–drug conjugates offer a bright future for patients with SCLC who fail first-line therapy. This review will focus on advancing treatment paradigms for SCLC in the era of precision medicine. Such a study might be helpful for pulmonologists and oncologists to manage precisely patients with SCLC. Full article

Background/Objectives: Cervical cancer (CC) is a significant global health challenge, particularly in low- and middle-income countries (LMICs), where limited access to human papillomavirus (HPV) vaccination and effective CC screening results in a majority of cases and fatalities among women. Moreover, existing vaccines do not target HPV-independent cancers. Current screening methods are expensive and time-consuming, with a limited emphasis on CC protein biomarkers. Therefore, we aimed to validate critical markers that allow the development of affordable point-of-care screening tests for resource-limited settings. Methods: This study first optimized a cell lysis and protein extraction protocol for CC cell lines and clinical cervical swabs. Subsequently, four proteins—topoisomerase II alpha (TOP2A), minichromosome maintenance complex component 2 (MCM2), valosin-containing protein (VCP), and cyclin-dependent kinase inhibitor 2A (p16INK4a)—were quantified in the resulting lysates using enzyme-linked immunosorbent assays, as well as in cervical tumors and squamous intraepithelial lesions (SILs) using immunohistochemistry for further validation. Results: Acetone precipitation allowed for efficient cell isolation, and radioimmunoprecipitation assay buffer yielded the highest protein recovery. VCP and p16INK4a were overexpressed across all cancer cell lines compared to primary cells. All four biomarkers were overexpressed in high-grade SIL (HSIL) swab specimens and tumor samples, including CC subtypes, G1–G3 tumor grades, and HSILs. Lastly, we showed that the proteins could accurately classify swabs and tissue specimens into clinically relevant groups. Conclusions: The quantitative analysis of these biomarkers, along with the subsequent sensitive and specific clinical classification, highlights their potential application in SIL early detection and CC prevention, particularly in LMICs. Full article

Antibody–drug conjugates (ADCs) are promising cancer therapeutics, but optimizing their cytotoxic payloads remains challenging. We present DumplingGNN, a novel hybrid Graph Neural Network architecture for predicting ADC payload activity and toxicity. Integrating MPNN, GAT, and GraphSAGE layers, DumplingGNN captures multi-scale molecular features using both 2D and 3D structural information. Evaluated on a comprehensive ADC payload dataset and MoleculeNet benchmarks, DumplingGNN achieves state-of-the-art performance, including BBBP (96.4% ROC-AUC), ToxCast (78.2% ROC-AUC), and PCBA (88.87% ROC-AUC). On our specialized ADC payload dataset, it demonstrates 91.48% accuracy, 95.08% sensitivity, and 97.54% specificity. Ablation studies confirm the hybrid architecture’s synergy and the importance of 3D information. The model’s interpretability provides insights into structure–activity relationships. DumplingGNN’s robust toxicity prediction capabilities make it valuable for early safety evaluation and biomedical regulation. As a research prototype, DumplingGNN is being considered for integration into Omni Medical, an AI-driven drug discovery platform currently under development, demonstrating its potential for future practical applications. This advancement promises to accelerate ADC payload design, particularly for Topoisomerase I inhibitor-based payloads, and improve early-stage drug safety assessment in targeted cancer therapy development. Full article

African Swine Fever Virus (ASFV) Topo II ATPase domain, resistant to conventional inhibitors (e.g., ICRF-187) due to M18/W19 steric clashes, was targeted via hierarchical virtual screening (Schrödinger) of the Chembridge library combined with MM/GBSA calculations. Five ligands (10012949, 40242484, 46712145, 15880207, and 33688815) showed high affinity, with 46712145 adopting symmetrical π–π stacking, hydrogen bonds, and alkyl interactions to bypass steric hindrance. Molecular dynamics simulations (100 ns) revealed ligand-induced flexibility, evidenced by elevated RMSD/Rg values versus the free protein. DCCM analysis highlighted enhanced anti-correlated motions between GHKL motifs and sensor domains in chain B/C, suggesting stabilization of a non-catalytic conformation to inhibit ATP hydrolysis. Free energy landscape (FEL) analysis showed 46712145 occupying a broad, shallow energy basin, enabling conformational adaptability, contrasting the narrow deep well of the free protein. This study proposes a symmetric ligand design strategy and conformational capture mechanism to block ATPase activity. Compound 46712145 demonstrates stable binding and dynamic regulation, providing a novel lead scaffold for anti-ASFV drug development. These findings establish a structural framework for combating ASFV through targeted ATPase inhibition. Full article

Background/Objectives: TDP-43 mutation-driven Amyotrophic Lateral Sclerosis (ALS) motor neuron disease is one of the most prominent forms (approximately 97%) in cases of sporadic ALS. Dysfunctional autophagy and lysosomal function are the prime mechanisms behind ALS. Mitoxantrone (Mito), a synthetic doxorubicin analog, is an inhibitor of DNA and RNA synthesis/repair via intercalating with nitrogenous bases and inhibiting topoisomerase II. The therapeutic potential of miRNAs associated with disease conditions has also been reported. This study explores the therapeutic potential of Mito along with miRNAs against mutated TDP-43 protein-induced proteinopathy in human-induced pluripotent stem cell (hiPSC)-derived human neural progenitor cells (hNPCs). Methods: HiPSCs mutated for TDP-43 were differentiated into hNPCs and used to explore the therapeutic potential of Mito at a concentration of 1 μM for 24 h (the identified non-cytotoxic dose). The therapeutic effects of Mito on miRNA expression and various cellular parameters such as mitochondrial dynamics, autophagy, and stress granules were assessed using the high-throughput Open Array technique, immunocytochemistry, flow cytometry, immunoblotting, and mitochondrial bioenergetic assay. Results: Mutated TDP-43 protein accumulation causes stress granule formation (G3BP1), mitochondrial bioenergetic dysfunction, SOD1 accumulation, hyperactivated autophagy, and ER stress in hNPCs. The mutated hNPCs also show dysregulation in six miRNAs (miR-543, miR-34a, miR-200c, miR-22, miR-29b, and miR-29c) in mutated hNPCs. A significant restoration of TDP-43 mutation-induced alterations could be witnessed upon the exposure of mutated hNPCs to Mito. Conclusions: Our study indicates that miR-543, miR-29b, miR-22, miR-200c, and miR-34a have antisense therapeutic potential alone and in combination with Mitoxantrone. Full article

In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs. Full article

Despite advances in vaccination and early detection, the total number of cases and deaths from cervical cancer has risen steadily in recent decades, making it the fourth most common type of cancer in women worldwide. Low-income countries in particular struggle with limited resources and treatment limitations for cervical cancer. Thus, effective medicines that are simple to manufacture are needed. The newly developed dual topoisomerase inhibitor P8-D6, with its outstanding ability to induce apoptosis, could be a promising option. In this study, the efficacy of P8-D6 in combination with radiochemotherapy against cervical carcinoma was investigated in established cell lines and in a translational approach in ex vivo patient cells by measuring the cytotoxicity, cell viability and caspase activity in vitro in 2D and 3D cell cultures. Treatment with P8-D6 resulted in significantly greater cytotoxicity and apoptosis induction compared to standard therapeutic cisplatin in both 2D and 3D cell cultures. Specifically, a considerably stronger anti-proliferative effect was observed. The treatment also led to morphological changes and a loss of membrane integrity in the 3D spheroids. Radiotherapy also benefited greatly from P8-D6 treatment. In fact, P8-D6 was a more potent radiosensitizer than cisplatin. Simple synthesis, favorable physicochemical properties and high potency make P8-D6 a promising cervical cancer drug candidate. Full article

The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect”, which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies. Full article

Irinotecan (CPT-11), an inhibitor of DNA topoisomerase I, stands as a pivotal therapeutic agent in oncology. However, its use is primarily constrained by side effects such as neutropenia and the onset of delayed diarrhea. Despite the effective management of neutropenia, CPT-11-induced diarrhea (CID) is often severe, leading to hospitalization, dosage adjustments, and in some cases, treatment discontinuation, which can significantly impact therapeutic outcomes. A multitude of pharmacological agents have been investigated in preclinical and clinical studies with the aim of reducing or preventing the onset of delayed diarrhea associated with CPT-11. This comprehensive review examines the underlying mechanisms of CPT-11-triggered delayed diarrhea and discusses the experimental medications and strategies that have been utilized to combat this adverse effect. This review encompasses an exploration of chemical formulations, the application of traditional Chinese medicine, and the advent of innovative drug delivery systems. It is anticipated that this article will serve as a valuable resource for both novice researchers in the realm of irinotecan chemotherapy and for those who are well-versed in the field, including experts and practicing clinicians. Full article

Cancer remains a leading cause of death worldwide, highlighting the urgent need for novel and more effective treatments. Natural products, with their structural diversity, represent a valuable source for the discovery of anticancer compounds. In this study, we screened 750 Antarctic extracts to identify potential inhibitors of human topoisomerase 1 (hTOP1), a key enzyme in DNA replication and repair, and a target of cancer therapies. Bioassay-guided fractionation led to the identification of palmitic acid (PA) as the active compound from the Antarctic sponge Artemisina plumosa, selectively inhibiting hTOP1. Our results demonstrate that PA irreversibly blocks hTOP1-mediated DNA relaxation and specifically inhibits the DNA religation step of the enzyme’s catalytic cycle. Unlike other fatty acids, PA exhibited unique specificity, which we confirmed through comparisons with linoleic acid. Molecular dynamics simulations and binding assays further suggest that PA interacts with hTOP1-DNA complexes, enhancing the inhibitory effect in the presence of camptothecin (CPT). These findings identify PA as a hTOP1 inhibitor with potential therapeutic implications, offering a distinct mechanism of action that could complement existing cancer therapies. Full article