Anti-cancer agents in medicinal chemistry最新文献

Breast cancer is the most prevalent malignant tumor among women globally, with breast cancer susceptibility genes (BRCA1 and BRCA2, BRCA1/2) mutations significantly increasing the risk of developing aggressive forms of the disease. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have shown promise in treating BRCA1/2-mutated breast cancer by exploiting deficiencies in homologous recombination (HR) repair. However, the emergence of acquired resistance poses a significant challenge. Our study examines the mechanisms of PARPi resistance in BRCA1/2-mutated breast cancer, synthesizing recent clinical advancements and identifying key resistance pathways, including HR recovery, DNA replication fork stability, and epigenetic modifications. We also highlight potential strategies to overcome these challenges to PARPi resistance, such as combination therapies and novel targets. Our comprehensive analysis aims to inform future clinical practices and guide the development of more effective treatment strategies.

Introduction: Heterocyclic compounds serve as the structural framework for many commercially available drugs and are well known for their antitumor properties.

Aim: This study aimed to evaluate the cytotoxic effects, apoptosis induction, changes in cell cycle progression, and gene expression alterations of new heterocyclic compounds and their precursors against the acute monocytic leukemia cell line THP-1 through in vitro experimentation and computational approaches.

Methods: The study employed cytotoxicity assays, flow cytometry analyses, gene expression evaluations, oral bioavailability studies, and molecular modeling. Among the compounds tested, 6, 25, and 26 demonstrated the greatest potency and selectivity, exhibiting substantially increased cytotoxicity (1.18 μM < IC₅₀ < 7.66 μM) against the THP-1 cell line. Investigations into apoptosis induction and cell cycle changes revealed that these compounds primarily caused an increase in the number of THP-1 cells undergoing apoptosis after 48 hours of treatment. Additionally, compounds 6 and 25 induced an accumulation of cells in the G0/G1 phase in the same cell line.

Results: Regarding gene expression, a shift in the expression profile of genes associated with apoptotic mechanisms was observed. Furthermore, in silico analysis revealed that these three active compounds potentially interact with histone deacetylase 8 (HDAC8), a protein known to be associated with cancer.

Conclusion: These findings underscore the potential of these compounds as candidates for the development of novel therapeutic approaches in oncology.

Background: Lung cancer is one of the most widespread malignancies among all types of cancers. There is uncertainty in its treatment because of the selectivity. The investigation is aimed to enhance therapeutic efficacy through targeted improvements in drug selectivity and reduced toxicity by analyzing well-accepted cyclooxygenase (COX)-2, which is an enzyme target and a known therapeutic target for anti-inflammatory and antitumor agents.

Objective: The objective of the present research was to identify the most suitable counterpart for celecoxib, which would produce synergistic effects and improve the selectivity index, safety, and efficacy of targeting cancer cells.

Methods: The HOPE-62 cancer cell line and noncancerous LLC-MK2 cell line were used to analyze the activity of the prepared formulations. The effectiveness was compared by calculating the half-maximal inhibitory concentration (IC50) values of carrageenan, celecoxib, and celecoxib embedded with carrageenan. The release pattern of celecoxib from the carrageenan matrix was also determined by using a trans-diffusion cell; moreover, the binding sites of carrageenan and celecoxib were also evaluated through in silico molecular docking studies.

Results: Carrageenan showed promising anticancer activity, with an IC₅₀ value of 17.3±2 μM against the HOPE- 62 cell line. When blended with celecoxib (15.6±2 μM), the combination achieved enhanced efficacy and improved selectivity over celecoxib alone (IC₅₀ of 10.3±1.5 μM). In noncancerous LLC-MK2 cells, the IC₅₀ values were observed to be significantly higher: 1484 ±6 μM in the combined formulation and with IC₅₀ values of 559±3 μM and 878±4 μM, respectively, in celecoxib and carrageenan alone.

Conclusion: The carrageenan-embedded celecoxib exhibited a significant increase in the selectivity index from 32 to 144, which suggests enhanced anticancer activity with a favorable safety profile. Initially, sustained release of celecoxib from the blend was at a higher rate, but steadily maintained rates were. The In-silico docking studies also supported the synergistic activity of the combined form through separate interaction patterns without interfering with others. These findings underscore the therapeutic potential of excipient-drug blending strategies to achieve synergistic effects, excellent selectivity, and reduced toxicity in cancer treatments.

Background: The smooth muscle α‑actin 2‑antisense 1 (ACTA2-AS1), also known as ZXF1, is an emerging cancer-associated long non-coding RNA (lncRNA) that has garnered significant attention in recent years. ACTA2-AS1 is situated on human chromosome 10 at location 10q23.31, comprising five exons and a single transcript. The aberrant expression of ACTA2-AS1 has been noted in 10 malignant tumors, correlating significantly with unfavorable clinicopathological characteristics and poor patient prognosis.

Objective: This review encapsulates recent progress in ACTA2-AS1 research, examining its expression profile, biological functions, molecular mechanisms, and anticipated influence on cancer diagnosis, treatment, and prognosis, emphasizing its potential as a novel therapeutic target based on lncRNA and its prognostic utility as a biomarker.

Methods: Based on a comprehensive search of the PubMed database for the biological function of lncRNA ACTA2-AS1 in malignant tumors, the current research is systematically summarized and critically analyzed.

Results: ACTA2-AS1 plays a complex role in various biological processes in tumor cells, encompassing proliferation, apoptosis, and cell cycle arrest. It also contributes to migration, invasion, epithelial-mesenchymal transition (EMT), and drug resistance. Mechanistically, ACTA2-AS1 influences oncogenic or tumor-suppressive effects via a complex regulatory network. It can adsorb specific 5 miRNAs as competitive endogenous RNAs (ceRNAs), thereby mitigating the suppression of downstream mRNA targets implicated in tumorigenesis (e.g., SOX7, KLF9, CXCL2, BCL2L11, etc.) and modulating their downstream signaling pathways (e.g., Wnt5a/PKC, SMAD3, mTOR, etc.), demonstrating a broad spectrum of dual roles in carcinogenesis and tumor suppression.

Conclusion: ACTA2-AS1 is a promising biomarker and molecular target for the treatment of cancer.

Background: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatment of anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.

Methods: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected by qPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferation activity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate the expression of p-ERK, p-AKT and Ki67 in mouse tumors.

Results: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drugresistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantly reduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo.

Conclusion: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibiting the reactivated RAS signaling pathway in anaplastic thyroid cancer.The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

Introduction: Although the development of SHP2 inhibitors has made striking progress, there is no inhibitor in clinical evaluation because of the potential side effects induced by poor drug distribution. Fluorescence imaging technology is widely used in the process of diagnosis and treatment of diseases because of the advantages of rapid imaging and non-destructive detection and might provide a new way to explore the mechanism of drug-target interactions in intact tissue.

Methods: A series of 2-quinolone derivatives as fluorescent inhibitors against SHP2 were designed and synthesized, and their spectral properties and biological activities were evaluated in this report. The representative compound 8A had excellent fluorescence properties (λ^emi_max : 562 nm, Stokes shift: 170 nm, fluorescence quantum yield: 0.072) and optical stability.

Results: Moreover, compound 8A emitted a blue signal in SHP2WT U2OS cells and inhibited the SHP2 enzyme abilities (IC₅₀: 20.16 ± 0.95 μM) without the extra combination of suitable fluorophores, linker, or selectiveactivated molecules.

Conclusion: Therefore, we hope that compound 8A could act as a lead to develop novel, convenient, and bifunctional chemical tools to explore the mechanism of drug-target interactions in intact tissue and promote the integrated research progress of diagnosis and treatment of SHP2 related diseases.

Talimogene laherparepvec (T-VEC), the first FDA-approved oncolytic viral therapy, has transformed cancer immunotherapy since its 2015 approval for unresectable melanoma. Engineered from Herpes Simplex Virus type 1 (HSV-1) with deletions in ICP34.5 and ICP47 genes and GM-CSF insertion, T-VEC selectively replicates within the tumor cells, inducing lysis and releasing tumor-derived antigens while stimulating systemic antitumor immunity through dendritic cell activation. Although extensively studied for melanoma, its potential extends beyond this malignancy, with emerging applications in breast cancer, Head and Neck Squamous Cell Carcinoma (HNSCC), and other solid tumors. This review synthesizes T-VEC's mechanism of action, leveraging dysregulated Ras signalling, impaired interferon pathways in cancer cells, its clinical outcomes, and safety profile across these indications. While prior literature emphasizes melanoma monotherapy and combinations with immune checkpoint inhibitors, less attention has been given to its efficacy in non-melanoma cancers and synergistic potential with chemotherapy or radiation therapy. By exploring recent trials, such as T-VEC with neoadjuvant chemotherapy in triple-negative breast cancer and pembrolizumab in HNSCC, highlighting its versatility. Comparative analysis with other oncolytic viruses like HF-10, oncorine (H101), and measles virus variants positions T-VEC within the virotherapy landscape. Key challenges-systemic delivery, immune clearance, and biomarker development for patient selection-are addressed alongside strategies to enhance immune modulation through novel combinations. This review underscores T-VEC's expanding role in cancer treatment, offering clinicians' and researchers' insights to optimize its therapeutic horizons across diverse malignancies.

Introduction: The presence of severe hypoxic stress can drive tumor growth, angiogenesis, and metastatic characteristics via up-regulated hypoxia-inducible factor 1-alpha (HIF-1α). Hence, targeting HIF-1α is considered a promising strategy, as increased HIF-1α activity is a key factor in the aggressive phenotype of malignancies. In this study, we aimed to investigate the anti-cancer effects of several flavonoids, both single and in combination with PX-478, in breast cancer cell lines.

Methods: We tested the effects of luteolin and PX-478, both alone and in combination, on HIF-1α level in breast cancer cells under hypoxia using the cell viability assay. To determine the rationale for the cell growth inhibition induced by the luteolin+PX-478 combination, we conducted experiments to assess cell survival, apoptosis, cell cycle, invasion, and migration under both normoxic and hypoxic conditions. Furthermore, we evaluated the effect of this combination on DNA damage response under hypoxic stress via Comet assay and immunofluorescence staining.

Results: Our findings revealed that the luteolin+PX-478 combination significantly suppressed the growth of MDA-MB-231 cells. In addition, we assessed time-dependent expression of HIF1α in MDA-MB-231 cells and observed that the combination of luteolin and PX-478 down-regulated the HIF-1α level. Finally, we found that the luteolin+PX-478 combination induced apoptosis and G2 cell cycle arrest and enhanced DNA damage response. This combination also sensitized breast cancer cells to ionizing radiation in hypoxic stress.

Discussion: The findings suggested that targeting HIF-1α with a combination of luteolin and PX-478 may provide a synergistic approach to suppressing tumor growth and enhancing therapeutic response under hypoxic conditions. The observed effects on apoptosis, cell cycle arrest, and DNA damage response indicated that this combination could be a promising strategy for overcoming hypoxia-induced resistance in breast cancer therapy.

Conclusion: Collectively, our results suggested the combination of luteolin and PX-478 to enhance the anticancer effects of PX-478 in breast carcinoma cells by impeding the cell growth and inducing DNA damage response under hypoxia.

Background: Breast cancer is an abnormal cell growth that develops in the breast and spreads throughout the body. Despite cancer being the second leading cause of death, survival rates are increasing as a result of progress in cancer screening and therapy. Breast cancer is the most frequently diagnosed cancer type among women, but in most cases, there are no obvious symptoms. Screening mammograms can be used for early detection of cancer. The size of the tumor and the extent of cancer spread determine the type of needed treatment. There are different forms of treatment, where targeted therapy is generally the least harmful. It targets specific characteristics of cancer cells, such as human epidermal growth factor receptor 2 (HER2). Tyrosine kinase inhibitors are effective targeted treatment of HER2 positive breast cancer. A newer class has emerged, cyclin dependent kinase (CDK4/6), which is used to treat metastatic breast cancer.

Objectives: Although CDK4/6 inhibitors class of therapy has revolutionized the treatment of metastatic breast cancer, some patients showed resistance and decreased efficacy. This study is the first to propose innovative computational strategies to improve the effectiveness and pharmacokinetic properties of existing HER2/CDK4/6 inhibitors anti-cancer agents. Through computer-aided drug design, the activity of existing breast cancer drug candidates has been tested. Structural modifications have been applied for in-silico optimization of their biological activity.

Methods: In this research, twenty-two analogues of the tested compounds have been proposed. Their biological activity and pharmacokinetic properties (ADMET) have been tested using BIOVIA Discovery Studio software.

Results: Out of the designed analogous compounds, seven proposed structures demonstrated superior efficacy compared to the original drugs. The research study docking studies revealed that modifications to lapatinib and tucatinib improved binding affinity to HER2 by 15-25%, with docking scores of -18.34 kcal/mol and -1.04 kcal/mol, respectively. Similarly, CDK4/6 inhibitors exhibited enhanced selectivity, with abemaciclib showing the highest binding energy of -13.2 kcal/mol. ADMET predictions suggested improved solubility and reduced toxicity risks compared to the original drugs.

Conclusion: The research study results demonstrate that the synthesis of more lipophilic analogues of lapatinib or tucatinib and, likewise designing of fluorinated derivatives of CDK4/6 inhibitors play a crucial role in improving the efficacy of these anti-cancer agents. These findings highlight the potential of the proposed modifications as promising candidates for further pharmacological and in vitro and in vivo clinical validation.