Recent patents on anti-cancer drug discovery最新文献

Background: Recent research has demonstrated the significance of Interferon Gamma- Inducible Protein 30 (IFI30), an interferon gamma-induced protein, in the immune response to cancerous growths. However, the relationship between IFI30 expression levels, patient prognosis, and tumor-infiltrating lymphocytes in clear cell renal cell carcinoma (ccRCC) remains inadequately defined.

Methods: To ascertain the potential link between IFI30 expression, clinical data, and overall survival (OS) in ccRCC patients, we employed diverse databases, which include TCGA, Gene Expression Profiling Interaction Analysis (GEPIA), and UALCAN. Furthermore, an in-depth analysis of the link between tumor-infiltrating immune cells (TIIC) and IFI30 was carried out using the TIMER, GEPIA, and TISIDB databases. Immunohistochemistry (IHC) was utilized to identify the IFI30 and PD-1 expression levels in a tissue microarray. Patents about molecular classification and drugs in ccRCC were reviewed through Worldwide Espacenet®.

Results: The expression of IFI30 demonstrated a strong association with sample type, lymph node stage, tumor grade, and cancer stage. Elevated IFI30 expression was linked to unfavorable Disease- Specific Survival (DSS) and Overall Survival (OS) outcomes (p <0.01). Furthermore, overexpression of IFI30 was strongly linked to immunomodulatory molecules, chemokines, and increased infiltration of regulatory T cells (Tregs), natural killer (NK) CD56 cells, T helper 1 (Th1) cells, cytotoxic T cells, and T helper cells. IHC analysis confirmed a robust correlation between IFI30 and PD-1 expression.

Conclusion: IFI30 is a prognostic biomarker for ccRCC patients. Targeting IFI30 may provide new strategies for cancer therapy and improve the prognosis of ccRCC patients.

Background: Colorectal cancer (CRC) is the third most common cancer worldwide, and its occurrence and progression are often regulated by genetic and hereditary factors. Ubiquitination and the associated ubiquitin-binding enzymes and ligases regulate the tumor microenvironment and antitumor immunity to mediate tumor pathogenesis and progression. In this study, we examined the molecular characteristics and immunomodulatory effects of ubiquitination-associated genes that mediate CRC prognosis.

Methods: The ubiquitination-related gene ubiquitin domain-containing protein 1 (UBTD1) was identified using bioinformatics and single-cell analyses. Subsequently, the ability of UBTD1 to predict CRC prognosis and immune checkpoint correlation was analyzed, the potential drug telatinib targeting UBTD1 was explored, and the correlation between UBTD1 and ferroptosis was analyzed. The role of UBTD1 in CRC and ferroptosis was verified using immunohistochemistry, gene knockout, western blot, cell cloning, and immunofluorescence.

Results: UBTD1 was identified as a significant prognostic and predictive gene for CRC and was involved in regulating immune checkpoint levels and immune cell function of CRC patients with CRC. High UBTD1 expression was found to enhance the presence of immune checkpoints that induce immune escape and inhibit ferroptosis onset. Telatinib may be a potential therapeutic drug targeting UBTD1.

Conclusion: Our study demonstrated that UBTD1 is a prognostic marker for CRC in the regulation of ubiquitination and the tumor immune microenvironment and may serve as a modulator of ferroptosis.

Background: BCL-2 was the first gene identified to have antiapoptotic effects, and venetoclax is an oral selective BCL-2 inhibitor, which has great potential in the treatment of patients with acute myeloid leukemia (AML) who are not candidates for intensive therapy. Notably, posaconazole, an oral antifungal drug, is also a strong factor that can affect blood venetoclax concentrations. To the best of our knowledge, the relationship between BCL-2 expression, posaconazole, and venetoclax, as well as their influence on treatment efficacy and the prognosis of patients with AML, has not been reported.

Objectives: In this single-center retrospective study, the relationship between BCL-2 expression and blood venetoclax concentration was analyzed in 35 patients with AML. After that, we explored the differences in curative effect, adverse reactions, and outcomes between patients with different BCL-2 expression levels and patients with different venetoclax concentration levels, respectively.

Methods: BCL-2 mRNA expression levels were examined by reverse transcription quantitative PCR. Blood venetoclax concentrations were measured using high-performance liquid chromatography- tandem mass spectrometry.

Results: The results revealed that among patients with AML, those with lower primary BCL-2 expression had a higher complete remission (CR) rate (p =0.005), overall response (OR) rate (p <0.0001), and progression-free survival time (p =0.04). Posaconazole was revealed to be a strong factor that was able to increase blood venetoclax concentration (p <0.001) and CR rate in the venetoclax plus posaconazole group compared to that in the venetoclax monotherapy group (p =0.002); however, no significant difference was identified in the occurrence of adverse reactions between these groups. Among low and high-blood venetoclax concentration groups, the event-free survival of the former group was significantly higher (p =0.013).

Conclusion: Higher levels of BCL-2 expression at initial diagnosis may have adverse effects on the efficacy and prognosis of patients, and higher levels of venetoclax concentration may advance the time of adverse reactions in patients, thus adversely affecting event-free survival (EFS).

Objective: This study aims to enhance the understanding of underlying mechanisms and potential therapies of the solute carrier organic anion (SLCO) transporter family in internal environment disorder (IED)-induced hepatocellular carcinoma (HCC). This could lead to new therapeutic strategies and offer new directions for the creation of new patents for HCC treatment products.

Methods: The orthotopic transplantation (OT), IED and IED-based OT (IED-OT) mouse models were established. Expression patterns of Slco4a1 and Slco1b2 were determined using reverse transcriptionquantitative polymerase chain reaction (RT-qPCR), western blotting (WB) and immunohistochemistry (IHC) in various tissues, including lung, stomach, liver, spleen, kidney, colon, small intestine, HCC tissues and adjacent non-cancerous tissues.

Results: Animals exhibited symptoms, including weight loss, lethargy, chills, dyspnea, altered hair texture, and gastrointestinal disturbances, confirming the successful establishment of the IED model. The analysis demonstrated differential expression and tissue-specific distribution of Slco4a1 and Slco1b2, which are associated with IED-induced changes. These alterations potentially disrupt organ transport functions, thereby promoting the development of HCC. Additionally, they suggest a role in rebalancing the tumor microenvironment and mitigating damage resulting from abnormal substance accumulation.

Conclusions: Changes in SLCO expression and distribution induced by IED may play pivotal roles in the development of HCC. These findings contribute insights that could inform novel therapeutic strategies against HCC.

Background: Lysyl oxidase-like 2 (LOXL2) is a metalloenzyme that catalyzes oxidative deamination ε-amino group of lysine. It has been found that LOXL2 is a promotor for the metastasis and invasion in kinds of tumors. Previous studies show that disulfide bonds are important components in LOXL2, and their bioactivity can be regulated by those bonds. In this way, a small molecule covalently binds to the thiol group of cysteine residue could be an effective way to change the function of LOXL2 by blocking the formation of the disulfide bond.

Objective: This investigation is aiming to screen covalent inhibitor for LOXL2.

Methods: Covalent molecule libraries of Life Chemical and Enamine were used. The structures of those molecules were optimized by using LigPrep module of Schrödinger. Then optimized by using the LigPrep module of Schrödinger to generate optimal conformations. For covalent docking, CovDock in Glide module was used for the virtual screening. Finally, wound-healing assays were performed to examine the effects of the potential inhibitors.

Results: Eight potential small molecules were selected by covalent docking from the databases (in total 7,908 candidates). ADMET evaluation indicated that all those eight small molecules satisfy the general standard. Furthermore, wound healing experiments showed that the compound (F50972176) significantly inhibits the migration of cancer cells.

Conclusion: Virtual screening and experimental verification methods were used to screen covalent inhibitors of LOXL2 by targeting functional disulfide bonds. The compound (F50972176) effectively inhibited the migration of esophageal squamous cell carcinoma cells.

Background: Angelica sinensis (Oliv.) Diels, a renowned traditional Chinese medicine, has gained widespread recognition for its antitumor properties. Further investigation is warranted to determine whether ligustilide (LIG), which is extracted from this plant, can effectively inhibit tumors.

Objectives: We delved into the impact of LIG on cholangiocarcinoma cells, aiming to unravel the mechanisms underlying its effects.

Materials and methods: Cholangiocarcinoma cells (HuccT1 and RBE) were exposed to varying concentrations of LIG (2, 5, 10, 15, 20 μg/mL) for 24, 48, and 72 h. After identifying differentially expressed genes, stable transcription strains were utilized to explore LIG's antitumor mechanism. The inhibitory effects of LIG (5 μg/mL, 48 h) were assessed by CCK-8, colony formation, wound healing, transwell migration, western blotting, and immunofluorescence. In vivo, experiments in NOG mice (Ac, Ac+LIG; five per group) evaluated LIG's antiproliferative efficacy (5 mg/kg, intraperitoneal injection, 18-day period).

Results: LIG significantly inhibited cell proliferation and migration with IC₅₀ 5.08 and 5.77 μg/mL in HuccT1 and RBE cell lines at 48h, increased the expression of E-cadherin while decreased N-cadherin and the protein of PI3K/AKT pathway. Silenced NDRG1 (N-Myc downstream- regulated gene 1) attenuated these effects. In vivo, the AC+LIG group (LIG, 5 mg/kg, qd, 18 d) exhibited smaller tumor volumes compared to the Ac group. The expression of Ki-67 was significantly downregulated in the AC+LIG group.

Conclusion: For the first time, our study has revealed that LIG holds therapeutic potential for treating cholangiocarcinoma. These findings hold promise for advancing innovative therapeutic approaches in the treatment of cholangiocarcinoma. LIG may serve as a useful patent for treating CCA.

Background: The tumor burden before chimeric antigen receptor T (CAR-T) cell therapy was one of the critical factors affecting the prognosis of lymphoma. It was a challenge to effectively reduce the tumor burden of relapsed/refractory large B-cell lymphoma with p53 mutation.

Objective: Here, we have presented a case of relapsed/refractory large B-cell lymphoma with p53 mutation being controlled by the treatment with daratumumab and venetoclax, followed by CAR-T cell therapy.

Case presentation: The patient was a 56-year-old female who was diagnosed with relapsed/ refractory diffuse large B cell lymphoma (DLBCL) transformed from follicular lymphoma. The patient was treated with daratumumab, venetoclax, and GEMOX (gemcitabine and oxaliplatin) under the guidance of high-throughput drug sensitivity analysis. We used a CD38 positive lymphoma cell line with p53 mutation to construct tumor models for validating the anti- lymphoma effect of the combination therapy of daratumumab and venetoclax.

Results: The patient achieved a complete metabolic response after treatment with daratumumab, venetoclax, and GEMOX. Then, she further achieved a complete molecular response after she subsequently received CAR-T cell therapy, and she has been living without a lymphoma recurrence. The results from the animal study showed that the combination of daratumumab and venetoclax could significantly enhance the antitumor effect on CD38-positive lymphoma with p53 mutation.

Conclusion: The results from our successful case and animal experiments provide new avenues for the treatment of relapsed/refractory large B-cell lymphoma with p53 mutation. Further clinical trials are reuqired to treat CD38-positive lymphoma with the combination of daratumumab and venetoclax.

Introduction: N6-methyladenosine (m⁶A) modifications of RNAs are associated with many cancer types. Nevertheless, the function of the m⁶A reader IGF2BP2 in oral squamous cell carcinoma (OSCC) has yet to be ascertained.

Aims: The objective of this investigation was to elucidate the role of IGF2BP2 in OSCC and delineate the associated mechanisms.

Methods: Elevated expression of IGF2BP2 was observed in OSCC, and this overexpression significantly correlated with adverse prognostic outcomes in patients with OSCC. In vitro analyses demonstrated that silencing of IGF2BP2 attenuated the proliferation, migration, and invasion capabilities of oral cancer cells while concurrently promoting apoptosis.

Results: In vivo experiments demonstrated that IGF2BP2 promoted OSCC growth. RNA-seq and m⁶A-seq were utilized to elucidate the downstream targets of IGF2BP2. Through bioinformatic analysis, we identified the long noncoding RNA (lncRNA) UCA1 as a target. IGF2BP2 was found to maintain the stability of UCA1 in an m⁶A-dependent manner by binding to m⁶A-modified UCA1 and plays an oncogenic role in OSCC through UCA1.

Conclusion: In conclusion, we identified IGF2BP2 as a prognostic biomarker of OSCC, and the IGF2BP2-UCA1 axis was found to promote OSCC progression and may perform as a novel therapeutic target.

Selinexor treats lung cancer, particularly non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). This review summarizes the prevalence and types of lung cancer and emphasizes the challenges associated with current treatments like resistance and limited effectiveness. Selinexor is a selective inhibitor of nuclear export (SINE) that has emerged as a potential therapy that targets the nuclear export of tumor suppressor proteins. The mechanisms of selinexor, its potential in combination therapies, and challenges like side effects and drug resistance are explained in this review. Key findings highlight the effectiveness of selinexor in preclinical studies, particularly against KRAS-mutant NSCLC and in combination with chemotherapy for SCLC. The review concludes with a discussion of future directions and underscores the potential of selinexor to improve the treatment strategies for lung cancer.

Background: Arginine plays significant and contrasting roles in breast cancer growth and survival. However, the factors governing arginine balance remain poorly characterized.

Objective: We aimed to identify the molecule that governs arginine metabolism in breast cancer and to elucidate its significance.

Methods: We analyzed the correlation between the expression of solute carrier family 7 member 3 (SLC7A3), the major arginine transporter, and breast cancer survival in various databases, including GEPIA, UALCAN, Metascape, String, Oncomine, KM-plotter, CBioPortal and PrognoScan databases. Additionally, we validated our findings through bioinformatic analyses and experimental investigations, including colony formation, wound healing, transwell, and mammosphere formation assays.

Results: Our analysis revealed a significant reduction in SLC7A3 expression in all breast cancer subtypes compared to adjacent breast tissues. Kaplan-Meier survival analyses demonstrated that high SLC7A3 expression was positively associated with decreased nodal metastasis (HR=0.70, 95% CI [0.55, 0.89]), ER positivity (HR=0.79, 95% CI [0.65, 0.95]), and HER2 negativity (HR=0.69, 95% CI [0.58, 0.82]), and increased recurrence-free survival. Moreover, low SLC7A3 expression predicted poor prognosis in breast cancer patients for overall survival. Additionally, the knockdown of SLC7A3 in MCF-7 and MDA-MB-231 cells resulted in increased cell proliferation and invasion in vitro.

Conclusion: Our findings indicate a downregulation of SLC7A3 expression in breast cancer tissues compared to adjacent breast tissues. High SLC7A3 expression could serve as a prognostic indicator for favorable outcomes in breast cancer patients due to its inhibitory effects on breast cancer cell proliferation and invasion.