Anti-cancer agents in medicinal chemistry最新文献

Aromatase, a crucial enzyme assigned for transforming androgen into estrogen, has a vital function in the advancement of drug-resistant breast cancers that respond to endocrine treatments. Aromatase (CYP19A1) is a monooxygenase from the cytochrome P450 family that is involved in the conversion of androgens to estrogens. Breast cancer cells express aromatase activity, indicating that the tumor cells may be able to produce local estrogen. By inhibiting aromatase, serum estrogen levels decrease, which, in turn, hinders estrogen-driven cancer cell growth in hormone receptor-positive breast cancer cases. In this sense, the introduction of novel aromatase inhibitors could be a significant step forward in the fight against cancer. This is especially true in hormone-dependent cancers. Many compounds have been introduced as aromatase inhibitors, classified as steroidal or nonsteroidal. However, it should be noted that these drugs have encountered resistance in numerous cases, particularly in recent years. Thus, the search for new aromatase inhibitor drugs has always been critical. Newly, there seems to be a surge of enthusiasm in the discovery and production of molecules with dual inhibitory effects, which can inhibit two or more enzymes simultaneously. This method enables a significant reduction in potential drug resistance. The design of these compounds has an opportunity to significantly boost the efficacy of anti-cancer treatments by causing synergistic effects. This article offers a review of newly developed aromatase inhibitors with potential anticancer effects.

Tumor-infiltrating immune cells (TIICs) have been identified as critical components in the development of cancer drug resistance. This review aims to discuss the various types of TIICs, such as macrophages and T cells, that have been linked to cancer drug resistance. Furthermore, we explore the mechanisms by which TIICs contribute to drug resistance and how these mechanisms may differ across various tumor types. Additionally, we examine the potential of immune checkpoint inhibitors in combination with traditional cancer therapies as a strategy to overcome TIIC-mediated cancer drug resistance. In conclusion, this review provides an in-depth analysis of the current knowledge on the role of TIICs in cancer drug resistance and highlights potential avenues for future research to develop more effective treatment strategies. The findings presented in this review emphasize the importance of understanding the complex interactions between cancer cells and the immune system in order to develop novel therapeutic approaches that can overcome TIIC-mediated cancer drug resistance.

Introduction: The emergence of acquired resistance to Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors (EGFR-TKIs) presents a significant barrier to effective treatment in lung adenocarcinoma. This study investigates the antitumor efficacy of FN-1501 and its potential synergistic interaction with Almonertinib (Alm) to combat this resistance.

Methods: The impact of FN-1501 on lung adenocarcinoma and its synergistic effects with Almonertinib (Alm) were assessed through flow cytometry, Western blot analysis, CCK-8 assays, and clonogenic formation assays. Additionally, transcriptome analysis and network pharmacology were employed to elucidate the functional mechanisms by which FN-1501 may reverse EGFR-TKI acquired resistance.

Results: FN-1501 demonstrated the ability to inhibit cell proliferation, induce apoptosis, and arrest the cell cycle. The combination of Alm and FN-1501 restored sensitivity in resistant cell lines. Mechanistic investigations indicated that this combination triggered ferroptosis via the FOXO1-mediated upregulation of NCOA4. In vivo experiments showed that the Alm+FN-1501 combination significantly inhibited tumor growth compared to either treatment alone.

Discussion: These results provide compelling evidence that targeting ferroptosis pathways could be a viable approach to overcoming resistance to EGFR-TKIs. The FOXO1/NCOA4 axis emerges as a critical component in this process, enhancing our understanding of the mechanisms underlying resistance. While these findings are promising, further research is needed to evaluate toxicity, pharmacokinetics, and the applicability of this strategy in a broader context of resistance. Identifying predictive biomarkers could help refine patient selection for this treatment approach.

Conclusion: FN-1501 exhibits significant antitumor activity and, when combined with Alm, effectively reverses EGFR-TKI resistance by inducing ferroptosis, highlighting its potential for clinical application.

Introduction: Glycosylation plays a crucial role in cellular processes such as recognition and signaling, and its dysregulation is associated with tumor progression. Alpha-1,3-mannosyltransferase (ALG3) is a key enzyme in N-glycosylation, and its aberrant expression has been implicated in various malignancies. However, the mechanisms underlying ALG3-driven oncogenesis and the identification of potential ALG3 inhibitors remain largely unexplored. This study aims to comprehensively investigate the oncogenic role of ALG3 across different cancer types and identify potential inhibitors through bioinformatics analysis and molecular dockingcoupled dynamics simulations.

Methods: Multiple cancer-related databases were analyzed to elucidate the oncogenic role of ALG and to assess its expression patterns, genetic alterations, and epigenetic regulation. Furthermore, molecular docking and dynamics simulations were employed to identify small-molecule inhibitors targeting the human ALG3.

Results: Our findings demonstrated a significant upregulation of ALG3 at both transcript and protein levels in cancerous tissues compared to normal ones. High ALG3 expression correlated positively with tumor stage, grade, and metastasis while negatively influencing patient survival. Genetic analysis revealed that amplification was the most common alteration in ALG3, whereas DNA methylation played a key role in its upregulation. Molecular docking and dynamics simulation identified two mannosyltransferase inhibitors, Opn and Clo, as potential inhibitors of ALG3, suggesting their therapeutic potential.

Discussion: This study highlights the oncogenic role of ALG3 in a pan-cancer model and identifies its potential inhibitors. Our findings provide valuable insights into ALG3-driven tumorigenesis and suggest that targeting ALG3 could be a promising strategy for cancer therapy.

Conclusion: The study first reported potential inhibitors of human ALG3 based on a molecular modelling approach. This opens the way for future experimental investigations of the testing of these lead compounds in ALG3-high cancer models.

Background: Hypopharyngeal Squamous Cell Carcinoma(HSCC) is associated with a poor prognosis due to challenges in early detection, early metastasis, and limited treatment options.

Objective: This study aims to investigate the effect of metformin on HSCC and identify potential prognostic factors associated with this carcinoma.

Methods: The effects of metformin in HSCC cells were tested by functional assays in vitro. A xenograft tumor model was established, which was further examined by H&E staining, immunohistochemistry, and transmission electron microscopy (TEM). RNA sequencing analysis was employed to investigate the effects of metformin on gene expression and associated pathways. Bioinformatic analysis was further conducted to elucidate potential mechanisms and their correlation with gene expression, the tumor immune microenvironment, and survival prognosis. Finally, we further assessed the effect on FaDu cells by knocking down lncAROD using siRNAs.

Results: The results demonstrated that metformin significantly reduced cell viability and migration, while promoting apoptosis and inducing cell cycle arrest in FaDu cells. WB analysis revealed that metformin inhibits the development of FaDu cells, possibly through the EMT pathway. In vivo studies indicate that metformin effectively inhibits tumor growth, promotes apoptosis, and autophagy. RNA-seq analysis revealed that metformin led to the upregulation of 1,697 genes and the downregulation of 858 genes, particularly highlighting a significant reduction in lncAROD, which were subsequently verified by qRT-PCR. Bioinformatic analysis demonstrated that lncAROD is highly expressed, with patients exhibiting higher levels of lncAROD showing poorer prognoses. Knockdown of lncAROD can reduce the proliferation, migration, and invasion of FaDu cells.

Conclusion: This finding presents a novel approach to the clinical management of HSCC, indicating that metformin influences various processes related to the growth and progression of HSCC. Specifically, it reduces lncAROD expression and inhibits tumor progression, suggesting that lncAROD may serve as a valuable biomarker for evaluating the prognosis of HSCC.

Background: Hepatocellular carcinoma (HCC) is a frequent cancer in the world and a highly fatal primary liver cancer. Berberine hydrochloride (BBH) has exhibited therapeutic potential against HCC with no toxicity and good anti-tumor effects.

Objective: The objective of this study is to investigate the role of BBH against HCC and elucidate its underlying mechanism.

Methods: In Hep3B and HCCLM3 cell lines, the anti-tumor effects of BBH were assessed using MTT, wound healing, and colony formation assays, which measure cell viability, migration, and proliferation, respectively. Protein expression linked to apoptosis and cell cycle regulation was examined using western blotting. RNA sequencing and metabolomics analysis were performed to identify the metabolic and molecular targets of BBH, which were further confirmed by molecular docking. Furthermore, a tumor model was established by subcutaneous injection of Hep3B cells into nude mice to determine whether BBH has antitumor effects in vivo.

Results: Following adose-dependent manner, BBH efficiently reduced the viability, and enhanced migration, inducing cell cycle arrest via downregulation of CDK1 and CCND1. It also induced apoptosis by downregulating BCL2 and upregulating BAX. RNA-seq analysis revealed that BBH-treated cells had differentially expressed genes enriched in amino acid metabolic pathways. Furthermore, metabolomics analysis depicted BBH-mediated inhibition of alanine, methionine, and glutamic acid biosynthesis in HCC cells. Protein-protein interaction (PPI) network analysis and molecular docking studies have identified DOT1L, SMYD2, and KMT2C as potential molecular targets for BBH. Tumor samples were stained with HE and KI67 immunohistochemistry, and BBH significantly inhibited tumor growth in vivo.

Conclusion: BBH may inhibit HCC tumorigenesis by disrupting amino acid metabolism and holds potential as a therapeutic agent for HCC.

Introduction: Therapeutic applications of camel milk in various human ailments have led to the investigation of camel milk against multiple cancers. However, the absence of its scientific evidence in skin cancer protection has prompted this new study's inception.

Methods: The study includes estimation of camel milk's chemopreventive potential on A431 cells and a twostage skin carcinogenesis model (Mus musculus). The in-vitro studies included MTT, scratch and flow cytometry assay to determine the anti-proliferative effects, anti-migratory ability and cell numbers in various cell cycle stages. In the in-vivo study, estimations of tumour morphology, biochemical alterations, along with a histopathological study were performed. Further, the milk was assessed for its anti-oxidative activities, followed by GCMS analysis for the investigation of potential compounds.

Results: The in-vitro results demonstrated camel milk's dose-dependent anti-proliferation, significant (p<0.001) cell migration inhibition, and conclusive G1/S phase cell cycle arrest. The in-vivo study revealed a notable reduction in tumour parameters and histopathological lesions in skin and liver tissues of camel milk-treated mice. Additionally, a marked decrease (p<0.005; 0.001) in LPO levels and an increase in GSH, catalase and SOD biochemical parameters were noted. Moreover, dose-dependent elevation (p<0.001) of milk's anti-oxidative activity (DPPH, ABTS, ferrous-ion & superoxide-anion chelating) and presence of numerous anti-oxidative and anticancer compounds was observed.

Discussions: The investigation highlightstranslational relevance of camel milk's in-vitro outcomes as supported by in-vivo findings. Moreover, GC-MS analysis and anti-oxidative potential underscore the mechanism behind the observed chemo-prevention.

Conclusions: The study reveals camel milk's significant chemo-preventive efficacy primarily due to its robust antioxidant properties, making it a promising adjunct skin cancer therapy.

Introduction: Approximately 30% of patients with diffuse large B-cell lymphoma (DLBCL) develop primary resistance or relapse, owing to the high heterogeneity and aggressive nature of the disease. Consequently, novel drugs are urgently needed to improve outcomes in patients who are resistant.

Methods: This study quantified the anti-proliferative effects of CCS1477 in vitro using the Cell Counting Kit-8 assay, 5-ethynyl-2'-deoxyuridine staining, and lactate dehydrogenase measurement. Flow cytometry and Western blot analyses were performed concurrently to investigate the induction of apoptosis and the activation of mitophagy. The efficacy and safety of CCS1477 were evaluated in in vivo models. To elucidate the mechanism, cell lines with EP300 knockdown and overexpression were established. Functional assays and Western blot analyses revealed that EP300 regulates apoptosis, mitophagy, and c-MYC-mediated drug-resistant phenotypes.

Results: This study demonstrated that CCS1477, a highly selective EP300/CBP bromodomain inhibitor, significantly suppressed the progression of diffuse large B-cell lymphoma. The study revealed that CCS1477 dosedependently inhibited the proliferation of diffuse large B-cell lymphoma cells and induced apoptosis and mitophagy. Mechanistically, EP300 downregulation promoted apoptosis and activated the PINK1-dependent mitophagy pathway while suppressing c-MYC-mediated drug resistance genes, ultimately inhibiting DLBCL cell proliferation. In animal models, CCS1477 significantly reduced tumor volume and extended doubling time, providing the first evidence of its in vivo antitumor activity against DLBCL.

Discussion: Through systematic in vitro and in vivo investigations, this study validated the significant therapeutic promise of EP300/CBP inhibitor CCS1477 for diffuse large B-cell lymphoma. However, the mechanistic basis for differential sensitivity across DLBCL subtypes, along with long-term efficacy and potential adverse effects, requires comprehensive investigation. Notably, EP300 has been verified as a novel prognostic biomarker and therapeutic target; this work establishes an innovative epigenetic-targeted strategy for relapsed/refractory diffuse large B-cell lymphoma.

Conclusion: By selectively targeting EP300, CCS1477 orchestrates a dual pro-death mechanism involving both intrinsic apoptosis execution and PINK1-driven mitochondrial clearance, resulting in significant inhibition of diffuse large B-cell lymphoma pathogenesis.

Introduction: Esophageal cancer often develops insidiously, with most cases diagnosed at an advanced stage. Currently, the pathogenesis of esophageal cancer remains unclear, treatment outcomes are poor, and the five-year survival rate is low. To tackle the significant clinical challenges of difficult diagnosis and unfavorable prognosis, it is crucial to actively investigate the disease's pathogenesis. This study explored the involvement of telomere shelterin protein TPP1 in the pathogenesis of esophageal cancer and identified potential therapeutic agents for its treatment.

Methods: The expression level of TPP1 protein in 54 pairs of esophageal cancer tissues and paired adjacent tissues was detected via immunohistochemistry. The impact of TPP1 silencing and Elbasvir administration on the growth of KYSE150 and TE1 esophageal cancer cell lines was assessed utilizing Cell Counting Kit-8 and colony formation assays. Cell migration was assessed through Transwell and scratch assays. Fluorescence microscopy was employed to observe autophagosome formation, while flow cytometry measured the fluorescence intensity of autophagy markers LC3 and P62 in TPP1-silenced KYSE150 and TE1 cells. Western blotting was utilized to examine the alterations in TPP1, the AKT-mTOR signaling pathway, autophagy-related proteins, and other associated proteins.

Results: TPP1 levels were notably elevated in esophageal squamous cell carcinoma tissues relative to adjacent normal tissues. Suppression of TPP1 substantially reduced the growth and movement of esophageal cancer cells in vitro, while triggering autophagy via the AKT-mTOR signaling pathway, highlighting TPP1's cancerpromoting function in esophageal cancer.

Discussion: Elbasvir effectively suppressed the growth and spread of KYSE150 and TE1 cell lines in vitro, downregulating TPP1 protein expression in relation to time and dosage. Additional investigations revealed that Elbasvir also inhibited the AKT-mTOR signaling axis and induced autophagy by targeting TPP1. Notably, rescue experiments demonstrated that 3-MA could reverse the inhibitory effects on proliferation, migration, and autophagy induced by TPP1 silencing or Elbasvir treatment in KYSE150 and TE1 cells.

Conclusion: TPP1 emerges as a compelling diagnostic indicator and a potential treatment focus in esophageal cancer, with Elbasvir offering promise as a novel therapeutic agent.

Introduction: The emergence of immune checkpoint inhibitors has revolutionized the treatment of cancer. Among these, the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis remains a critical target. However, resistance to current biologics necessitates the development of novel Small- Molecule Inhibitors (SMIs) with distinct mechanisms and improved pharmacological profiles. This review provides a comprehensive analysis of recent progress in PD-L1-targeting SMIs, including original compounds from our laboratory.

Methods: We conducted a structured literature review using electronic databases such as PubMed, Scopus, and Web of Science. Articles published between 2015 and 2025 were included based on relevance to small-molecule PD-L1 inhibitors in cancer immunotherapy. Key data were extracted and synthesized regarding molecular design strategies, mechanisms of action, pharmacokinetics, and therapeutic efficacy. Compounds synthesized in our laboratory (Compounds 5-10 [A56]) were evaluated using in vitro assays, including PD-L1/PD-1 binding inhibition, cancer cell viability assays, and gene expression profiling.

Results: Recent SMIs exhibit diverse functional profiles: direct blockade of PD-1/PD-L1 interaction, intracellular PD-L1 modulation, and transcriptional downregulation. Notably, Compound 7 demonstrated significant suppression of PD-L1 mRNA expression, while Compounds 9 and 10 (A56) achieved nanomolar-level binding affinity. These findings reflect innovative approaches to overcoming immune resistance and enhancing antitumor responses.

Discussions: Our findings underscore a trend toward multifunctional PD-L1-targeting SMIs that operate through both extracellular and intracellular mechanisms. Compounds from our laboratory represent potential leads for further optimization and clinical translation. However, challenges remain regarding oral bioavailability, metabolic stability, and immune-related adverse events.

Conclusion: Small-molecule PD-L1 inhibitors offer a promising avenue for expanding cancer immunotherapy. Our review highlights key advances and introduces novel small-molecule PD-L1 inhibitors with strong potential for future development, particularly in combination regimens.