Anti-cancer agents in medicinal chemistry最新文献

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: Chemotherapy-induced gastrointestinal reactions are common in non-small cell lung cancer (NSCLC) patients undergoing carboplatin-based chemotherapy. Jianpi Yiwei granules (JPYW), a traditional Chinese medicine (TCM) formula, can alleviate these symptoms.

Materials and methods: This multi-center, randomized, double-blind, placebo-controlled trial enrolled 136 NSCLC patients scheduled for carboplatin-based chemotherapy. Participants were randomly assigned to the treatment group (JPYW with standard antiemetic drugs) and the control group (placebo with standard antiemetic drugs). The complete control rate of nausea and vomiting was assessed using the Visual Analog Scale (VAS) and patient diaries. Control of anorexia, bloating, constipation, and quality of life was measured using the Functional Living Index-Emesis scale and the Brief Fatigue Inventory (BFI).

Results: The primary objective of this study was to assess the efficacy of JPYW in alleviating non-vomiting digestive symptoms, such as nausea and anorexia, in NSCLC patients receiving carboplatin-based chemotherapy. The secondary objective was to evaluate its effect on improving bloating, constipation, quality of life, and safety.

Discussion: Previous studies have shown that Chinese herbs, such as ginger, are effective in treating chemotherapy- induced nausea and vomiting (CINV). JPYW, a multi-component TCM formula, contains active compounds from Codonopsis pilosula and Atractylodes macrocephala. JPYW exerts anti-inflammatory and prokinetic effects that can synergistically regulate gastrointestinal functions. Preliminary observations confirmed the safety of JPYW combined with standard chemotherapy.

Conclusion: The current findings contribute to the treatment of adverse reactions to tumor chemotherapy and are expected to improve the quality of life for chemotherapy patients.

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: 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.

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.

Introduction: Pancreatic adenocarcinoma is a highly aggressive cancer with a poor prognosis and a five-year survival rate of just 13%. Its asymptomatic onset, rapid progression, and resistance to therapy make it challenging to treat. Transforming Growth Factor-β (TGF-β) signaling, particularly through TGF-β Receptor 1 (TGF-βR1/ALK-5), plays a major role in tumor progression by inducing Epithelial-Mesenchymal Transition (EMT), immune evasion, and apoptosis resistance. Targeting ALK-5 is a promising strategy for therapeutic intervention.

Methods: Twenty-nine synthetic flavonols were designed to inhibit ALK-5 and docked using Schrodinger's Glide XP. The compounds were synthesized via a green, one-pot method and characterized using 1H-NMR, 13CNMR, Mass Spectrometry, CHN analysis, and IR spectroscopy. The anti-cancer activity was evaluated against MiAPaCa-2 pancreatic cancer cells by measuring GI50, TGI, and LC50. ALK-5 inhibition was quantified using the ADP-Glo® Kinase Assay, assessing ATP transfer.

Results: RFL-1 showed the strongest binding affinity (-9.38 kcal/mol) at ALK-5's active site and the highest kinase inhibition (ATP transfer: 3.67%), outperforming quercetin (9.22%). It also demonstrated an IC50 of 14.92 ± 3.54 μM. Ten flavonols exhibited strong cytotoxicity (GI50 < 10 μM), while four others showed moderate activity (GI50 = 23-26 μM).

Discussion: RFL-1 and related flavonols (RFL-12, RFL-20, RFL-25, RFL-28) effectively inhibited ALK-5 and suppressed the growth of pancreatic cancer cells. Their dual activity supports further development as targeted anti-cancer agents.

Conclusion: Synthetic flavonols, particularly RFL-1, show promise as ALK-5 inhibitors and potential therapies for pancreatic adenocarcinoma, warranting further in vivo validation.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is one of the most prevalent hematological malignancies with high mortality. G1 to S phase transition 1 (GSPT1), a key translation termination factor involved in protein synthesis, has been implicated in tumor progression. This study aimed to investigate the effectiveness and underlying mechanisms of the GSPT1 degrader SJ6986 in DLBCL.

Methods: The TCGA and GTEx datasets were utilized to assess the expression of GSPT1 in DLBCL. The viability and proliferation of DLBCL cells were detected using the Cell Counting Kit-8 (CCK-8) assay. Cell apoptosis was detected via flow cytometry. The expression of GSPT1 was evaluated using qRT-PCR and Western blot. Xenograft mouse models were employed to explore the in vivo therapeutic potential of SJ6986. RNA sequencing was used to explore the potential mechanism of SJ6986 in DLBCL.

Results: This study first identified that GSPT1 is highly expressed in DLBCL and demonstrated that its genetic knockdown significantly suppressed the activity of DLBCL cells. Furthermore, it was found that SJ6986 effectively reduced the proliferation of DLBCL cells, induced cell apoptosis, and inhibited tumor growth in vivo without significant toxicity. Mechanistically, RNA sequencing analysis showed that the endoplasmic reticulum (ER) stress was significantly triggered following SJ6986 treatment, and SJ6986 was found to activate the ER stress-related apoptosis in DLBCL cells.

Discussion: Our findings suggested that SJ6986 exerts its anti-tumor effects in DLBCL and activates the ER stress-related apoptotic signaling. These results supported SJ6986 as a viable anticancer drug for treating DLBCL. Future studies should further investigate its mechanism and evaluate its clinical application value.

Conclusions: This study validated the efficacy and safety of SJ6986 in treating DLBCL and discovered its role in inducing ER stress and subsequent apoptosis, offering a promising therapeutic option for DLBCL patients.

Introduction: Prostate cancer (PRAD) remains a leading malignancy with limited prognostic biomarkers and therapeutic targets. PRR22, a proline-rich protein-coding gene, has a role in PRAD that remains undefined. This study is the first to systematically investigate the clinical relevance and mechanistic implications of PRR22 in PRAD.

Methods: PRR22 expression was analyzed in TCGA-PRAD (n = 501), GSE55945, and the Human Protein Atlas datasets. Prognostic value was assessed via Kaplan-Meier and multivariate Cox analyses. Mechanistic insights were derived from GSEA, immune infiltration profiling, MSI/mRNA-si correlations, and drug sensitivity analysis. Experimental validation was performed via qRT-PCR in PRAD cell lines.

Results: PRR22 was significantly upregulated in PRAD tissues compared to normal tissues (p < 0.001) and independently predicted shorter progression-free survival (HR = 1.82, p = 0.009). Novel associations were identified between PRR22 and TGF-β signaling, immune evasion (e.g., LAG3 upregulation), microsatellite instability (MSI), and stemness (mRNA-si). High PRR22 correlated with resistance to multiple drugs (e.g., bicalutamide, vorinostat).

Discussion: PRR22 overexpression in PRAD is linked to poor prognosis and immune regulation, suggesting its potential as a prognostic biomarker and therapeutic target. Future research should focus on clinical validation and on exploring the molecular mechanisms underlying PRR22's role in PRAD.

Conclusion: PRR22 is a novel, independent prognostic biomarker and actionable therapeutic target in PRAD, linking tumor aggressiveness to immune microenvironment remodeling and drug resistance. These findings establish PRR22 as a candidate for clinical implementation in risk stratification and targeted therapy.