Unveiling the impact of glutathione (GSH) and p53 gene deletion on tumor cell metabolism by amino acid and proteomics analysis.

Background: Tumor cell inhibition is a pivotal focus in anti-cancer research, and extensive investigations have been conducted regarding the role of p53. Numerous studies have highlighted its close association with reactive oxygen species (ROS). However, the precise impact of the antioxidant glutathione (GSH) in this context remains inadequately elucidated. Here, we will elucidate the anti-cancer mechanisms mediated by p53 following treatment with GSH. Methods: In this study, we employed a p53 gene knockout approach in SW480 colorectal cells and conducted comprehensive analyses of 20 amino acids and proteomics using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Results: These analyses unveiled profound alterations in amino acids and proteins triggered by GSH treatment, shedding light on novel phenomena and delineating the intricate interplay between GSH and cellular proteins. The deletion of the p53 gene exerts a profound influence on tumor cell proliferation. Moreover, tumor cell proliferation is significantly affected by elevated GSH levels. Importantly, in the absence of the p53 gene, cells exhibit heightened sensitivity to GSH, leading to inhibited cell growth. The combined therapeutic approach involving GSH and p53 gene deletion expedites the demise of tumor cells. It is noteworthy that this treatment leads to a marked decline in amino acid metabolism, particularly affecting the down-regulation of methionine (Met) and phenylalanine (Phe) amino acids. Among the 41 proteins displaying significant changes, 8 exhibit consistent alterations, with 5 experiencing decreased levels and 3 demonstrating increased quantities. These proteins primarily participate in crucial cellular metabolic processes and immune functions. Conclusions: In conclusion, the concurrent administration of GSH treatment and p53 gene deletion triggers substantial modifications in the amino acid and protein metabolism of tumor cells, primarily characterized by down-regulation. This, in turn, compromises cell metabolic activity and immune function, ultimately culminating in the demise of tumor cells. These newfound insights hold promising implications and could pave the way for the development of straightforward and efficacious anti-cancer treatments.

Remarkable response to capmatinib in a patient with intrahepatic cholangiocarcinoma harboring TFG-MET fusion.

Dysregulation of mesenchymal-epithelial transition factor (MET) gene due to amplification, mutation, and fusion has been reported in various types of human cancers. Recently, the efficacy of small-molecule tyrosine kinase inhibitors (TKIs) targeting MET has been demonstrated in a wide range of MET-dysregulated tumors. The majority of biliary tract cancers including intrahepatic cholangiocarcinoma (iCCA) are diagnosed at an advanced stage, and the utility of conventional chemotherapy is limited. Here, we present a case of metastatic iCCA harboring TFG-MET gene fusion, which demonstrated a remarkable response to treatment with capmatinib, a selective MET inhibitor. The patient was a 46-year-old man diagnosed with iCCA with hepatic, intraabdominal lymph nodes, and peritoneal metastases. Comprehensive genomic profiling (CGP) revealed TFG-MET gene fusion in his tumor. After becoming refractory to standard chemotherapy, he received capmatinib, which resulted in a marked shrinkage of the liver masses and lymph node metastases, as well as a drastic decrease in serum CA19-9 level. Our case reinforces the importance of CGP in exploring targeted therapy and supports the potential role of capmatinib in the treatment of tumors harboring MET fusions.

Dramatic response to crizotinib through MET phosphorylation inhibition in rare TFG-MET fusion advanced squamous cell lung cancer.

With the widespread use of next-generation sequencing (NGS) for solid tumors, mesenchymal-to-epithelial transition factor (MET) rearrangement/fusion has been confirmed in multiple cancer types. MET amplification and MET exon 14 skipping mutations induce protein autophosphorylation; however, the pathogenic mechanism and drug sensitivity of MET fusion remain unclear. The following report describes the clinical case of a patient diagnosed with squamous lung cancer bearing a TFG-MET gene fusion. In vitro assays demonstrated MET phosphorylation and oncogenic capacity due to the TFG-MET rearrangement, both of which were inhibited by crizotinib treatment. The patient was treated with crizotinib, which resulted in sustained partial remission for more than 17 months. Collectively, cellular analyses and our case report emphasize the potential of MET fusion as a predictive biomarker for personalized target therapy for solid tumors.

Efficacy and tolerability of capmatinib in a very elderly patient with metastatic NSCLC harboring a MET exon 14 mutation.

We report the case of an 87-year-old female patient who was diagnosed with metastatic non-small-cell lung cancer harboring MET exon 14 skipping mutation (MET ex14) and PD-L1 expression of 60%. A first-line treatment with atezolizumab was started with primary resistance. Then, a second-line treatment with capmatinib, a selective type Ib MET tyrosine kinase inhibitor, was started, achieving a partial response. The patient is still alive and on treatment with capmatinib 300 mg twice daily after 20 months, with a good tolerability and no evidence of disease progression.In summary, our patient experienced a long-lasting response (>18 months) with capmatinib as second-line treatment. Further analyses evaluating the efficacy and tolerability of MET tyrosine kinase inhibitors are warranted, especially in the elderly, a non-small-cell lung cancer population whose tumors could more frequently harbor MET ex14 mutation.

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Predicting MET exon 14 skipping mutation in pulmonary sarcomatoid carcinoma by whole-tumour texture analysis combined with clinical and conventional contrast-enhanced computed tomography features.

Background: Pulmonary sarcomatoid carcinoma (PSC) is a rare, highly malignant type of non-small cell lung cancer (NSCLC) with a poor prognosis. Targeted drugs for MET exon 14 (METex14) skipping mutation can have considerable clinical benefits. This study aimed to predict METex14 skipping mutation in PSC patients by whole-tumour texture analysis combined with clinical and conventional contrast-enhanced computed tomography (CECT) features. Methods: This retrospective study included 56 patients with PSC diagnosed by pathology. All patients underwent CECT before surgery or other treatment, and both targeted DNA- and RNA-based next-generation sequencing (NGS) were used to detect METex14 skipping mutation status. The patients were divided into two groups: METex14 skipping mutation and nonmutation groups. Overall, 1,316 texture features of the whole tumour were extracted. We also collected 12 clinical and 20 conventional CECT features. After dimensionality reduction and selection, predictive models were established by multivariate logistic regression analysis. Models were evaluated using the area under the curve (AUC), and the clinical utility of the model was assessed by decision curve analysis. Results: METex14 skipping mutation was detected in 17.9% of PSCs. Mutations were found more frequently in those (I) who had smaller long- or short-axis diameters (P=0.02, P=0.01); (II) who had lower T stages (I, II) (P=0.02); and (III) with pseudocapsular or annular enhancement (P=0.03). The combined model based on the conventional and texture models yielded the best performance in predicting METex14 skipping mutation with the highest AUC (0.89). The conventional and texture models also had good performance (AUC =0.83 conventional; =0.88 texture). Conclusions: Whole-tumour texture analysis combined with clinical and conventional CECT features may serve as a noninvasive tool to predict the METex14 skipping mutation status in PSC.

Prominent response to savolitinib monotherapy in high-grade fetal adenocarcinoma with MET amplification and concurrent brain metastasis: a case report.

Background: Mesenchymal-epithelial transition (MET) represents a potential therapeutic target in various cancers, with amplification of the MET gene identified in a subset of patients with pulmonary adenocarcinomas. However, MET gene amplification is rarely observed in high-grade fetal adenocarcinoma (H-FLAC). Case Description: Here we present a novel case of a patient diagnosed with stage IV H-FLAC harboring MET amplifications and treated with savolitinib. The 69-year-old male patient, who presented with a primary complaint of cough and white sputum, had a history of hypertension for over 10 years and a 45-year smoking history. The patient received savolitinib monotherapy treatment due to brain metastases. Despite the omission of radiotherapy for asymptomatic brain metastases, a notable response to savolitinib therapy was observed, with a partial response (PR) achieved after 4 weeks and a reduction in the brain tumor. At the time of the submission of this report, the patient received over 24 weeks of savolitinib treatment, and was maintained PR. The patient was still undergoing treatment. This highlights the potential clinical benefits of targeted therapy against MET amplification in H-FLAC. Conclusions: H-FLAC harboring MET amplification and brain metastasis is rare. Treatment with savolitinib monotherapy resulted in a PR, providing preliminary insights to the efficacy of savolitinib for H-FLAC with MET amplification.

Joint DNA-RNA-based NGS for diagnosis and treatment of a rare CD47-MET fusion lung adenocarcinoma which was immunoresistant and savoltinib-sensitive: a case report.

Targeted therapy and immunotherapy are both important in the treatment of non-small-cell lung cancer (NSCLC). Accurate diagnose and precise treatment are key in achieving long survival of patients. MET fusion is a rare oncogenic factor, whose optimal detection and treatment are not well established. Here, we report on a 32-year-old female lung adenocarcinoma patient with positive PD-L1 and negative driver gene detected by DNA-based next-generation sequencing (NGS). A radical resection of the primary lesion after chemotherapy combined with PD-1 checkpoint inhibitor administration indicated primary immuno-resistance according to her pathological response and rapid relapse. A rare CD47-MET was detected by RNA-based NGS, which was confirmed by fluorescence in situ hybridization. Multiplex immunofluorescence revealed a PD-L1 related heterogeneous immunosuppressive microenvironment with little distribution of CD4+ T cells and CD8+ T cells. Savolitinib therapy resulted in a progression-free survival (PFS) of >12 months, until a new secondary resistance mutation in MET p.D1228H was detected by re-biopsy and joint DNA-RNA-based NGS after disease progression. In this case, CD47-MET fusion NSCLC was primarily resistant to immunotherapy, sensitive to savolitinib, and developed secondary MET p.D1228H mutation after targeted treatment. DNA-RNA-based NGS is useful in the detection of such molecular events and tracking of secondary mutations in drug resistance. To this end, DNA-RNA-based NGS may be of better value in guiding precise diagnosis and individualized treatment in this patient population.

PRRX1 silencing is required for metastatic outgrowth in melanoma and is an independent prognostic of reduced survival in patients.

Paired related homeobox 1 (PRRX1) is an inducer of epithelial-to-mesenchymal transition (EMT) in different types of cancer cells. We detected low PRRX1 expression in nevus but increased levels in primary human melanoma and cell lines carrying the BRAFV600E mutation. High expression of PRRX1 correlates with invasiveness and enrichment of genes belonging to the EMT programme. Conversely, we found that loss of PRRX1 in metastatic samples is an independent prognostic predictor of poor survival for melanoma patients. Here, we show that stable depletion of PRRX1 improves the growth of melanoma xenografts and increases the number of distant spontaneous metastases, compared to controls. We provide evidence that loss of PRRX1 counteracts the EMT phenotype, impairing the expression of other EMT-related transcription factors, causing dysregulation of the ERK and signal transducer and activator of transcription 3 (STAT3) signaling pathways, and abrogating the invasive and migratory properties of melanoma cells while triggering the up-regulation of proliferative/melanocytic genes and the expression of the neural-crest-like markers nerve growth factor receptor (NGFR; also known as neurotrophin receptor p75NTR) and neural cell adhesion molecule L1 (L1CAM). Overall, our results indicate that loss of PRRX1 triggers a switch in the invasive programme, and cells de-differentiate towards a neural crest stem cell (NCSC)-like phenotype that accounts for the metastatic aggressiveness.

An extremely rare case of primary alveolar rhabdomyosarcoma in the central nervous system.

Background: Alveolar rhabdomyosarcoma (ARMS) shows a predilection for the peripheral extremities and is very rarely identified as a primary in the brain. Here, we report a case of ARMS with multiple lesions exclusively within the central nervous system (CNS). Case Description: A 20-year-old man presented to our hospital with a gradually increasing headache and disturbance of consciousness. Neuroimaging showed hydrocephalus and multiple tumor lesions, including in the brainstem and cerebellum, with uniform gadolinium enhancement on T1-weighted magnetic resonance imaging, as well as spinal cord seeding. Cerebrospinal fluid (CSF) analysis showed a slightly elevated cell count (6/µL; normal, <5/µL) and highly elevated protein (153 mg/dL). In addition, atypical cells were cytologically identified in the CSF. No other laboratory findings were abnormal. Emergency ventricular drainage was performed to control cerebral pressure, followed by a biopsy to confirm the diagnosis. Histological examination revealed a fascicular arrangement of oval cells with eosinophilic cytoplasm and tumor cells with pleomorphic nuclei and prominent nucleoli. Immunohistochemical studies showed negative results for glial fibrillary acidic protein and positive results for desmin and myogenin. In addition, molecular analysis revealed that this tumor had the H3F3A p.Lys28Met mutation and no paired box (PAX)3-forkhead box O1 (FOXO1) or PAX7-FOXO1 fusion genes. ARMS was, therefore, diagnosed. Chemotherapy and radiotherapy were subsequently initiated, but tumor growth could not be controlled, and the patient died 6 months after surgery. Conclusion: This report describes an extremely rare case of ARMS arising exclusively within the CNS.

Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer.

Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.

Capmatinib plus nazartinib in patients with EGFR-mutated non-small cell lung cancer.

PURPOSE: This phase 1b/2 trial evaluated the efficacy and safety of capmatinib plus nazartinib in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: In phase 1b, patients with progression on first-/second-generation EGFR-TKIs received escalating doses of capmatinib 200-400 mg bid plus nazartinib 50-150 mg qd. Once the MTD/RP2D was declared, phase 2 commenced with patient enrollment into groups according to mutation status and prior lines of treatment: group 1 (fasted; EGFR-TKI resistant; 1-3 prior lines; EGFRL858R/ex19del; any T790M/MET); group 2 (fasted; EGFR-TKI naïve; 0-2 prior lines; de novo T790M+; any MET); group 3 (fasted; treatment-naïve; EGFRL858R/ex19del; T790M-; any MET); group 4 (with food; 0-2 prior lines; EGFRL858R/ex19del; any T790M/MET). Primary endpoints in phase 2 were investigator-assessed overall response rate (ORR) per RECIST v1.1 (groups 1-3), safety, and tolerability of the combination with food (group 4). Efficacy was assessed by T790M and MET status for a subgroup of patients. RESULTS: The RP2D was capmatinib 400 mg bid plus nazartinib 100 mg qd. In phase 2 (n = 144), the ORR was 28.8 %, 33.3 %, 61.7 %, and 42.9 % in groups 1 (n = 52), 2 (n = 3), 3 (n = 47), and 4 (n = 42), respectively. In group 1 +phase 1b RP2D, the ORR was 45.8 %, 26.2 %, 37.9 %, and 32.4 % in MET+ (n = 24), MET- (n = 42), T790M+ (n = 29), and T790M- (n = 34) patients. Most common any-grade treatment-related adverse events (≥25 %; n = 144) were peripheral edema (54.9 %), nausea (41.7 %), diarrhea (34.0 %), and maculopapular rash (25.0 %). CONCLUSION: Capmatinib plus nazartinib showed antitumor activity in patients with EGFR-TKI-resistant, EGFR-mutated NSCLC. The overall safety profile was acceptable. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT02335944.

The BDNF Val66Met polymorphism serves as a potential marker of body weight in patients with psychiatric disorders.

Brain-derived neurotrophic factor (BDNF) is a predominant neurotrophic factor in the brain, indispensable for neuronal growth, synaptic development, neuronal repair, and hippocampal neuroplasticity. Among its genetic variants, the BDNF Val66Met polymorphism is widespread in the population and has been associated with the onset and aggravation of diverse pathologies, including metabolic conditions like obesity and diabetes, cardiovascular ailments, cancer, and an array of psychiatric disorders. Psychiatric disorders constitute a broad category of mental health issues that influence mood, cognition, and behavior. Despite advances in research and treatment, challenges persist that hinder our understanding and effective intervention of these multifaceted conditions. Achieving and maintaining stable body weight is pivotal for overall health and well-being, and the relationship between psychiatric conditions and body weight is notably intricate and reciprocal. Both weight gain and loss have been linked to varying mental health challenges, making the disentanglement of this relationship critical for crafting holistic treatment strategies. The BDNF Val66Met polymorphism's connection to weight fluctuation in psychiatric patients has garnered attention. This review investigated the effects and underlying mechanisms by which the BDNF Val66Met polymorphism moderates body weight among individuals with psychiatric disorders. It posits the polymorphism as a potential biomarker, offering prospects for improved monitoring and therapeutic approaches for mental illnesses.

Non B Cell-Derived Immunoglobulins in Lung Epithelial Cells and Lung Cancer.

As the locus for air exchange, lung tissue is perpetually exposed to a significant quantity of foreign pathogens. Consequently, lung has developed a refined and intricate immune system. Beyond their physical and chemical barrier roles, lung epithelial cells can contribute to immune defence through the expression of Toll-like receptors (TLRs) and other pattern recognition receptors, along with the secretion of cytokines. Emerging evidence demonstrates that lung epithelial cells can generate and secrete immunoglobulins (Igs), including IgM, IgA, or IgG, thus performing antibody function. Moreover, malignantly transformed lung epithelial cells have been discovered to produce high levels of Ig, predominantly IgG, which do not fulfill the role of antibodies, but instead carries out tumour-promoting activity. Structural analysis has indicated that the biological activity of IgG produced by lung cancer cells differs from that of Igs produced by normal lung epithelial cells due to the unique glycosylation modification. Specifically, the sialylated IgG (SIA-IgG), characterised by a non-traditional N-glycosylation modification at the Asn162 site of Igγ CH1, is highly expressed in tumour stem cells. It has been demonstrated that SIA-IgG relies on this unique sialylation modification to promote tumorigenesis, metastasis, and immune evasion. Current results have proven that the Ig produced by lung epithelial cells has multifaceted biological activities, including immune defence functions under physiological conditions, while acquiring tumour-promoting activity during malignant transformation. These insights possess potential for the diagnosis and treatment of lung cancer as novel biomarkers and targets.

Spatiotemporal regulation of the hepatocyte growth factor receptor MET activity by sorting nexins 1/2 in HCT116 colorectal cancer cells.

Cumulative research findings support the idea that endocytic trafficking is crucial in regulating receptor signaling and associated diseases. Specifically, strong evidence points to the involvement of sorting nexins (SNXs), particularly SNX1 and SNX2, in the signaling and trafficking of the receptor tyrosine kinase (RTK) MET in colorectal cancer (CRC). Activation of hepatocyte growth factor (HGF) receptor MET is a key driver of CRC progression. In the present study, we utilized human HCT116 CRC cells with SNX1 and SNX2 genes knocked out to demonstrate that their absence leads to a delay in MET entering early endosomes. This delay results in increased phosphorylation of both MET and AKT upon HGF stimulation, while ERK1/2 (extracellular signal-regulated kinases 1 and 2) phosphorylation remains unaffected. Despite these changes, HGF-induced cell proliferation, scattering, and migration remain similar between the parental and the SNX1/2 knockout cells. However, in the absence of SNX1 and SNX2, these cells exhibit increased resistance to TRAIL-induced apoptosis. This research underscores the intricate relationship between intracellular trafficking, receptor signaling, and cellular responses and demonstrates for the first time that the modulation of MET trafficking by SNX1 and SNX2 is critical for receptor signaling that may exacerbate the disease.

Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy.

Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.

Virtual Screening, Molecular Dynamics Simulation, and Bioactivity Assessment Validate T13074 as a Dual-Target EGFR/c-Met Inhibitor.

OBJECTIVES: The objective of this study is to identify dual-target inhibitors against EGFR/c-Met through virtual screening, dynamic simulation, and biological activity evaluation. This endeavor is aimed at overcoming the challenge of drug resistance induced by L858R/T790M mutants. METHODS: Active structures were gathered to construct sets of drug molecules. Next, property filtering was applied to the drug structures within the compound library. Active compounds were then identified through virtual screening and cluster analysis. Subsequently, we conducted MTT antitumor activity evaluation and kinase inhibition assays for the active compounds to identify the most promising candidates. Furthermore, AO staining and JC-1 assays were performed on the selected compounds. Ultimately, the preferred compounds underwent molecular docking and molecular dynamics simulation with the EGFR and c-Met proteins, respectively. RESULT: The IC50 of T13074 was determined as 2.446 µM for EGFRL858R/T790M kinase and 7.401 nM for c-Met kinase, underscoring its potential in overcoming EGFRL858R/T790M resistance. Additionally, T13074 exhibited an IC50 of 1.93 µM on the H1975 cell. Results from AO staining and JC-1 assays indicated that T13074 induced tumor cell apoptosis in a concentration-dependent manner. Notably, the binding energy between T13074 and EGFR protein was found to be -90.329 ± 16.680 kJ/mol, while the binding energy with c-Met protein was -139.935 ± 17.414 kJ/mol. CONCLUSION: T13074 exhibited outstanding antitumor activity both in vivo and in vitro, indicating its potential utility as a dual-target EGFR/c-Met inhibitor. This suggests its promising role in overcoming EGFR resistance induced by the L858R/T790M mutation.

Design, Synthesis and Evaluation of A Novel Teoptinib Derivative as an Effective Anti-Hepatocellular Carcinoma Agent.

BACKGROUND & PURPOSE: Hepatocellular Carcinoma (HCC) is a type of liver cancer known for its poor prognosis and high mortality. Teoptinib is a highly selective MET inhibitor that has been used in the treatment of liver cancer. Although good progress has been made in clinical treatment, further improvement is still needed. In this study, a series of novel Teoptinib derivatives were synthesized and evaluated as anti-cancer agents for the treatment of liver cancer, and an oral nanodrug delivery system was also explored. METHODS: A series of novel Teoptinib derivatives were synthesized, and an oral nanodrug delivery system was also explored. HPLC, high-resolution mass spectrometer and NMR were used to determine the structure and molecular formula of the synthesized compounds. Zeta potential assay was used to access the particle size distribution and zeta potential of the nanoparticles. MTT assay, cell colony formation assay, cell apoptosis inhibition assay, cell scratch assay, and the MHCC-97H xenograft model of nude mice assay were used to evaluate the in vitro and in vivo anti-tumor activity of the synthesized compounds. RESULTS: Compound (R)-10 showed the best antitumor activity with 0.010 µM of the IC50 value against MHCC-97H, a human liver cancer cell line with high c-Met expression. The MHCC-97H xenograft model of nude mice assay showed that nano-prodrug of compound (R)-10 exhibited good in vivo activity with 87.67% of the TGI at the dosage of 8 mg/kg. CONCLUSION: We designed and synthesized a series of c-Met inhibitors containing different side chains and chiral centers as anti-liver cancer agents. Among them, compound (R)-10 shows a promising effect as a lead molecule for further study in the treatment of liver cancer. The successful incorporation of (R)-10 into a novel oral nanodrug delivery system highlights the importance of effective drug delivery systems for enhanced therapeutic efficacy.