Anti-cancer agents in medicinal chemistry最新文献

Introduction: Estrogen receptor (ERα) is known to be a legitimate therapeutic target for the treatment of ER-positive breast cancer. Although selective estrogen receptor degraders (SERDs) like fulvestrant suppress ER signaling, their limited bioavailability challenges efficacy. Additionally, activating mutations in the ERα mediate resistance to endocrine therapy.

Methods: To elucidate the structural activity relationship within a chromene-based scaffold, we conducted pharmacophore mapping and Gaussian field-based 3D QSAR modelling. The most active analogue was docked into the ERα ligand binding domain (PDB ID: 6V8T) and then subjected to molecular dynamics simulations and molecular mechanics generalized born surface area (MM/ GBSA) binding-free energy calculations.

Results: The pharmacophore mapping produces a five-point hypothesis, of which HHHRR_1 achieved the highest survival score (6.423) with a fitness score close to 3. Using HHHRR_1, a Gaussian Field-based 3D QSAR model with strong internal predictivity (cross-validated q2 is 0.8) and an excellent external validation was developed (r2 is 0.94). Compound 18 demonstrated stable binding in the ERα pocket with a ΔGbind MM/GBSA value of -67.03 kcal/mol, outperforming fulvestrant with a ΔGbind MM/GBSA of -64.76 kcal/mol. These findings suggest compound 18 engages critical ERα interactions more effectively with the target.

Discussion: The integrated modelling approach, like pharmacophore mapping, 3D QSAR, docking, and molecular dynamics, elucidated molecular characteristics essential for potent ERα degradation. Compound 18, having superior binding affinities, implies that optimizing these features on a chromene scaffold can yield new oral SERDs with enhanced therapeutic potential.

Conclusion: Based on the results of pharmacophore mapping, docking, molecular simulation, and 3D QSAR studies, we have designed a new set of chromene scaffold-based derivatives as potent SERDs along with their predicted activity.

Background: Solid lipid nanoparticles (SLNs) are submicron carriers with great promise in revolutionizing cancer therapy. They offer a potential solution to the side effects of conventional anticancer drugs, such as systemic toxicity and non-specific distribution. Taxanes, a widely used class of anticancer agents, have been increasingly incorporated into nano-lipid formulations (NLFs) to enhance their therapeutic index.

Objective: Designing optimal SLN formulations with enhanced drug loading capacity (DLC%), entrapment efficiency (EE%), and controlled drug release profiles is a significant challenge in pharmaceutical nanotechnology. This review, the first of its kind, systematically explores the key factors influencing EE%, DLC%, and the release behavior of Taxane-loaded SLNs. It provides a comprehensive and updated perspective, equipping you with the latest knowledge in this field.

Methods: This narrative review adopts a comprehensive approach to examine the formulation variables that affect EE%, including lipid type, drug properties, surfactants, co-surfactants, emulsifiers, and conjugates. It also outlines the critical parameters that influence drug release, such as particle size, co-loaded drugs, types of lipids and emulsifiers, surface modifiers, release media, and environmental conditions, including pH. The review process involved thoroughly analyzing existing literature and studies in pharmaceutical nanotechnology.

Results: Numerous studies demonstrate that EE% is significantly affected by the physicochemical properties of both the drug and lipid matrix and the choice and concentration of surfactants (e.g., Poloxamer, Tween-80, Solutol HS-15, lecithin). Certain modifications, such as conjugation with Hyaluronic acid, Chitosan derivatives, and PEGylation, tend to lower EE% but improve targeted release. Incorporation of compounds like α-lipoic acid, Ketoconazole, or co-loaded PTX and DTX results in a slower drug release profile. Conversely, siRNA incorporation often accelerates drug release. The release rate is also modulated by environmental pH and the nature of the lipid carriers. Ideal SLN formulations demonstrate high EE% and DLC% along with sustained and controlled release of Taxanes.

Conclusion: Multiple formulation and environmental factors influence EE%, DLC%, and the drug release behavior of Taxane-loaded SLNs. Understanding these variables is not just important, but it is the key to rationalizing effective and stable nano-lipid formulations in cancer therapy. It is a fascinating and crucial area of study that demands our attention.

Introduction: Prostate cancer is a leading cause of cancer-related mortality in men worldwide, and the treatment of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. CD24, a glycosylated cell surface protein, plays a critical role in tumor progression and immune evasion. This review focuses on the role of CD24 in prostate cancer pathogenesis, particularly its interaction with mutant p53, and explores potential therapeutic implications.

Methods: Through a systematic search of the PubMed, Web of Science, and Embase databases (2015-2025), using the following structured search terms: (CD24 OR "CD24 antigen") AND ("prostate cancer" OR "prostatic neoplasms") AND ("mutant p53" OR "TP53 mutation") AND ("targeted therapy" OR immunotherapy), relevant studies were identified and screened according to PRISMA guidelines.

Results: CD24 overexpression was significantly associated with high Gleason scores, metastasis, and poor prognosis. Mechanistically, CD24 promotes tumor progression by destabilizing p53 through the disruption of ARF-NPM interactions and by synergizing with mutant p53. Preclinical studies indicate that therapies targeting CD24, such as CAR-T cells and nanoparticle-based drug delivery systems, demonstrate potent anti-tumor effects.

Discussion: The CD24-p53 axis is amplified in mCRPC and interacts with androgen receptor signaling, while tumor microenvironment factors further enhance treatment resistance.

Conclusion: CD24 and mutant p53 represent promising therapeutic targets in metastatic castration-resistant prostate cancer (mCRPC). Translating these targeting strategies into clinical practice may help overcome current therapeutic challenges and improve patient outcomes.

Breast cancer threatens the health of women worldwide. However, the use of chemotherapy for breast cancer is prone to generating side effects and drug resistance. Therefore, identifying natural compounds with anticancer activity is a better solution to the problem of drug resistance. Oleanolic acid (OA), a kind of pentacyclic triterpenoid, is widely studied and used in the field of oncology. It has biological activity against breast cancer and has few side effects on normal cells. OA can be used as a frame for chemical modification to synthesize new compounds for the development of new drugs. At present, some OA derivatives with anti-breast cancer biological activity have been proven clinically, while others have emerged as candidates. This review aims to provide a comprehensive understanding of the mechanisms of oleanolic acid and its derivatives on breast cancer from previous studies.

Introduction/objective: Radiotherapy (RT) is a standard cancer treatment that may be associated with problems such as ineffectiveness and side effects. This study investigated ginsenosides' radiosensitizing and radioprotective properties and their metabolites during RT.

Methods: This study searched databases including PubMed/MEDLINE, Scopus, Embase, and Cochrane Library for articles before January 28, 2025. After specifying the inclusion and exclusion criteria, relevant articles were imported into EndNote software and screened. Then, the data were recorded in tables and analyzed.

Results: After the screening process, 28 articles were included. Ginsenosides exhibited radioprotective effects in normal tissues by reducing oxidative stress, preserving mitochondrial integrity, enhancing DNA repair, modulating inflammatory pathways, and supporting hematopoiesis. Key compounds such as Rg1, Rg3, and Rh2 promoted tissue regeneration and protected against radiation-induced organ damage. In tumour cells, ginsenosides enhance radiosensitivity by increasing reactive oxygen species (ROS), disrupting mitochondrial function, inducing DNA damage and cell cycle arrest, and promoting apoptosis. They also inhibited tumour progression via nuclear factor kappa B (NF-κB) suppression and immune activation, reducing angiogenesis and metastasis. These dual actions suggest their potential to improve radiotherapy outcomes.

Discussion: Ginsenosides revealed dual roles as radioprotective and radiosensitizing agents, highlighting their potential in improving RT outcomes. However, the limited clinical data and lack of ginseng extract studies indicate the need for future clinical studies to establish optimal dosing, safety, and relevance for humans.

Conclusion: The findings of both in vivo and in vitro studies indicated that ginsenosides enhance RT and provide protective effects against the harmful impacts of ionizing radiation.

The challenging subtype of breast cancer known as Triple-Negative Breast Cancer (TNBC) is characterized by the absence of HER2 expression, progesterone receptors, and estrogen receptors. TNBC is linked to a harsh treatment trajectory, elevated rates of recurrence, and restricted therapeutic alternatives. The mainstay of treatment for TNBC has historically been conventional chemotherapy, especially taxanes like Docetaxel. However, the effectiveness of these drugs is frequently compromised by systemic toxicity and resistance mechanisms. The development of Nanosomal Docetaxel Lipid Suspension (NDLS) offers a promising alternative, designed to enhance Docetaxel's therapeutic index by improving solubility, reducing side effects, and optimizing tumor-targeted drug delivery. NDLS has potential as a delivery system for additional chemotherapy drugs or combination treatments. This study addresses the cellular and molecular causes of TNBC, emphasizes the drawbacks of traditional treatments, and offers a thorough examination of NDLS in preclinical and clinical settings. This review provides a thorough analysis of NDLS in TNBC, laying the groundwork for further studies and therapeutic applications.

Introduction: Laryngeal cancer is a common malignant tumor of the head and neck worldwide. This study aimed to identify potential risk genes, with a particular focus on GPR65, and to investigate its functional mechanism in pathogenesis of laryngeal cancer.

Materials and methods: Comprehensive analyses, including scRNA-seq analysis, genome-wide association study (GWAS), eQTL, and TCGA data, were conducted to identify risk genes for laryngeal cancer and characterize the function of these risk genes. Next, qRT-PCR, immunohistochemistry, cell proliferation, cell migration, and invasion assays were employed to verify the expression of GPR65 and its function in laryngeal squamous cell carcinoma (LSCC) in vitro.

Results: Single-cell analysis screened 416 highly expressed genes in CD8+ central memory T cells (CD8_CM). Mendelian randomization (MR) analysis identified GPR65 as a crucial gene in the development of laryngeal cancer. GPR65 expression was significantly elevated in the tumor tissues compared to normal tissues, with particularly high levels observed in stage IV HNSCC. In vitro, LSCC cell lines (TU686 and Hep-2) exhibited marked upregulation of GPR65 relative to normal epithelial cells, and siRNA-mediated silencing of GPR65 suppressed the proliferation, migration, and invasion of LSCC cells. Furthermore, GPR65 expression showed a positive correlation with immune cell infiltration, particularly CD8+ T cells and M1 macrophages.

Discussion: This study identified GPR65 as a potential risk gene for laryngeal cancer through single-cell transcriptomics and MR analyses and provided novel evidence of its involvement in the development of the cancer.

Conclusion: The present findings showed that highly expressed GPR65 was a tumor-promoting gene in laryngeal cancer, showing its clinical value as a potential therapeutic target.

Lin28 is a pivotal RNA-binding protein that regulates the biogenesis of let-7 microRNAs, which play a crucial role in the post-transcriptional regulation of oncogenes in cancer. The Lin28/let-7 axis is integral to the regulation of key cellular processes such as proliferation, differentiation, and apoptosis. Lin28 promotes the upregulation of oncogenes, including MYC, RAS, and HMGA2, by inhibiting the maturation of let-7, thereby facilitating tumor initiation, progression, and metastasis. Consequently, targeting the Lin28/let-7 interaction has emerged as a promising therapeutic strategy, particularly for malignancies that lack specific molecular targets. This approach holds potential for downregulating oncogene expression and inhibiting tumor progression. Through a comprehensive review of the literature, this article classifies Lin28/let-7 inhibitors into three categories: CSD/ZKD inhibitors, non- CSD/ZKD inhibitors, and let-7 restorers. CSD/ZKD inhibitors, such as TPEN and KCB3602, function by binding to the CSD or ZKD domains of Lin28, thereby inhibiting its activity. Non-CSD/ZKD inhibitors, including compounds like C1632 and Simvastatin, have been identified as molecules that can reduce Lin28 activity, though their binding sites remain unknown. Let-7 restorers, on the other hand, do not directly target Lin28 but instead work indirectly by modulating the activity of associated molecules, such as Zcchc11 and Zcchc6, thereby promoting the restoration of let-7 expression levels. Notable examples of these include IPA-3 and FPA124. This review summarizes recent advances in the development of Lin28/let-7 inhibitors and their therapeutic potential, providing an important reference for ongoing research on Lin28 inhibitors in cancer therapy.

Background: Herpes zoster (HZ) is a common complication in patients with malignant tumors (MT), impacting prognosis. Immunocompromised states due to malignancy or treatment increase HZ risk. However, comprehensive assessments of HZ's clinical features and its impact on prognosis in these patients are limited, general conclusions are challenging, prompting a systematic review and meta-analysis to better understand the relative risk of HZ in malignancy.

Objective: To assess the clinical features and prognostic factors of HZ in cancer patients through systematic review and meta-analysis. The study aimed to calculate the relative risk of HZ in malignancy and analyze factors affecting prognosis, such as age, gender, tumor type, and treatment.

Methods: A systematic search in PubMed (2016-2024) identified studies on HZ and malignancy. Two reviewers independently screened and selected studies, extracting data on study characteristics, population demographics, and outcomes. Statistical heterogeneity across the studies was addressed using random-effects models, while subgroup analyses were performed to identify potential sources of heterogeneity.

Results: Out of the 633 records reviewed, 13 studies satisfied the eligibility criteria and were incorporated into the meta-analysis. The combined relative risk for any type of cancer was found to be 1.82(95% CI: 1.29,2.57). The combined relative risk for any solid tumors was 1.63(95% CI: 1.08,2.46). The combined relative risk for any haematological cancer was 3.43(95% CI: 1.33,8.86). The combined analysis of all treatment modalities (including Radiotherapy, Chemotherapy, Immunosuppression, HSCT) shows a significant overall effect with a risk ratio of 1.78(95%CI: 1.59,2.00).

Conclusion: Cancer patients have increased HZ risk due to immunosuppression from the malignancy and its treatment, especially in hematological cancers and those undergoing stem cell transplantation.