Epigenetic Targets and Their Inhibitors in the Treatment of Idiopathic Pulmonary Fibrosis

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 289, С. 117463 - 117463

Опубликована: Март 1, 2025

Язык: Английский

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CD47 blockade reverses resistance to HDAC inhibitor by liberating anti-tumor capacity of macrophages

Journal of Experimental & Clinical Cancer Research, Год журнала: 2025, Номер 44(1)

Опубликована: Фев. 24, 2025

Abstract Background Targeting oncogenic histone modification by deacetylase inhibitors (HDACis) demonstrates promising prospects in clinical cancer treatment, whereas a notable proportion of patients cannot benefit from HDACi therapy. This study aims to explore how influences the tumor microenvironment, order identify potential targets for reversing resistance therapies. Methods Macrophage infiltration was compared between HDACi-responding and HDACi-nonresponding patients. The impact HDACis on phagocytic capacity macrophages investigated through macrophage-tumor cell co-culture system. CD47 expression lines patient-derived organoids evaluated quantitative polymerase chain reaction (QPCR) flow cytometry. Mechanistic studies were conducted co-immunoprecipitation (co-IP) chromatin immunoprecipitation (ChIP). synergistic effect neutralizing antibody assessed subcutaneous murine models. Bioinformatics approaches adopted analyze macrophage determines prognostic significance Results High is determinant therapeutic non-response HDACi, who did not respond exhibit massive tumor-associated (TAMs). TAM depletion reversed Mechanistically, impaired against cells epigenetically upregulating expression. Reciprocally, HDACi-upregulated polarized towards pro-tumor M2 phenotype SIRPα ligation. In tumor-bearing mice, monotherapy only marginally delayed progression, while concurrent neutralization exhibited potent anti-tumor re-educating TAMs tumoricidal phenotype. patients, found determine TAMs. Conclusions Our offers rationale targeting or blocking sensitize therapies

Язык: Английский

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Design and biological evaluation of dual tubulin/HDAC inhibitors based on millepachine for treatment of prostate cancer

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 268, С. 116301 - 116301

Опубликована: Март 1, 2024

Язык: Английский

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Targeted Protein Degradation (TPD) for Immunotherapy: Understanding Proteolysis Targeting Chimera-Driven Ubiquitin-Proteasome Interactions

Bioconjugate Chemistry, Год журнала: 2024, Номер 35(8), С. 1089 - 1115

Опубликована: Июль 11, 2024

Targeted protein degradation or TPD, is rapidly emerging as a treatment that utilizes small molecules to degrade proteins cause diseases. TPD allows for the selective removal of disease-causing proteins, including proteasome-mediated degradation, lysosome-mediated and autophagy-mediated degradation. This approach has shown great promise in preclinical studies now being translated treat numerous diseases, neurodegenerative infectious cancer. review discusses latest advances its potential new chemical modality immunotherapy, with special focus on innovative applications cutting-edge research PROTACs (Proteolysis TArgeting Chimeras) their efficient translation from scientific discovery technological achievements. Our also addresses significant obstacles prospects this domain, while offering insights into future immunotherapeutic applications.

Язык: Английский

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Small Molecule Inhibitors Targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for Cancer Immunotherapy (2020-2024)

European Journal of Medicinal Chemistry, Год журнала: 2024, Номер 283, С. 117141 - 117141

Опубликована: Дек. 5, 2024

Язык: Английский

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Discovery of a potential hematologic malignancies therapy: Selective and potent HDAC7 PROTAC degrader targeting non-enzymatic function

Acta Pharmaceutica Sinica B, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

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Epigenomic Echoes—Decoding Genomic and Epigenetic Instability to Distinguish Lung Cancer Types and Predict Relapse

Epigenomes, Год журнала: 2025, Номер 9(1), С. 5 - 5

Опубликована: Фев. 5, 2025

Genomic and epigenomic instability are defining features of cancer, driving tumor progression, heterogeneity, therapeutic resistance. Central to this process epigenetic echoes, persistent dynamic modifications in DNA methylation, histone modifications, non-coding RNA regulation, chromatin remodeling that mirror underlying genomic chaos actively influence cancer cell behavior. This review delves into the complex relationship between these illustrating how they collectively shape genome, affect repair mechanisms, contribute evolution. However, dynamic, context-dependent nature changes presents scientific ethical challenges, particularly concerning privacy clinical applicability. Focusing on lung we examine specific patterns function as biomarkers for distinguishing subtypes monitoring disease progression relapse.

Язык: Английский

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Establishing a Prognostic Model Correlates to Inflammatory Response Pathways for Prostate Cancer via Multiomic Analysis of Lactylation‐Related Genes

International Journal of Genomics, Год журнала: 2025, Номер 2025(1)

Опубликована: Янв. 1, 2025

Prostate cancer (PCa) continues to pose substantial clinical challenges, with molecular heterogeneity significantly impacting therapeutic decision‐making and disease trajectories. Emerging evidence implicates protein lactylation—a novel epigenetic regulatory mechanism—in oncogenic processes, though its prognostic relevance in PCa remains underexplored. Through integrative bioinformatics interrogation of lactylation‐associated signatures, we established correlations using multivariable feature selection methodologies. Initial screening via differential expression analysis (limma package) coupled Cox proportional hazards modeling revealed 11 survival‐favorable regulators 16 hazard‐associated elements linked biochemical recurrence. To enhance predictive precision, ensemble machine learning frameworks were implemented, culminating a 10‐gene lactylation signature demonstrating robust discriminative capacity (concordance index = 0.738) across both primary (TCGA‐PRAD) external validation cohorts (DKFZ). Multivariable regression confirmed the score’s independence, exhibiting prominent associations clinicopathological parameters including tumor staging metastatic potential. The developed clinical‐molecular nomogram achieved superior accuracy (C − > 0.7) through synergistic integration biological covariates. Tumor microenvironment deconvolution uncovered distinct immunological landscapes, high‐risk stratification correlating enriched stromal infiltration immunosuppressive phenotypes. Pathway enrichment analyses implicated chromatin remodeling processes cytokine‐mediated inflammatory cascades as potential mechanistic drivers divergence. Therapeutic vulnerability profiling demonstrated response patterns: low‐risk patients exhibited enhanced immune checkpoint inhibitor responsiveness, whereas subgroups showed selective chemosensitivity docetaxel mitoxantrone. Functional PC‐3 models AK5 silencing induced proapoptotic effects, suppressed migration invasion, modulated regulation CD276 coexpression. These multimodal findings position dynamics, particularly AK5‐mediated pathways, promising targets biomarkers management.

Язык: Английский

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ALK-based dual inhibitors: Focus on recent development for non-small cell lung cancer therapy

European Journal of Medicinal Chemistry, Год журнала: 2025, Номер 291, С. 117646 - 117646

Опубликована: Апрель 17, 2025

Язык: Английский

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The combination of HDACi encapsulated liposomal vaccines with oncolytic peptide QR-KLU induces an immune-mediated abscopal effect for cancer immunotherapy

Journal of Pharmaceutical Investigation, Год журнала: 2025, Номер unknown

Опубликована: Апрель 30, 2025

Abstract Purpose Tumor vaccines have been showing a relatively weak response rate in cancer patients. The combination of liposomal with different kinds agents could affect arms the immune system and/or tumor microenvironment (TME), potentially leading to more satisfactory responses. In this paper, we investigated effects using containing Pam 2 - mucin 1 (MUC1) antigens, αGalCer and pan-histone deacetylase inhibitor (HDACi) SAHA oncolytic peptide QR-KLU for immunotherapy. Methods physical properties contained was identified such as nanoparticle diameter polydispersity index, zeta potential. Cell based assays were conducted evaluate cell toxicity lytic QR-KLU. vivo B16F10-MUC1 tumor-bearing mouse model used anti-cancer effect by therapy vaccines. Results showed improved than vaccine alone on cells. cells sensitive killed at low micromolar levels order test enhanced therapy, intratumorally injected into model, then mice sequentially treated SAHA@liposomal via intraperitoneal administration. combined demonstrated greatest reductions volume systemic compared or monotherapy. We further found treatment T-cell dependent, also resulted an abscopal regression distal non-treated lesions. Conclusion Our research that represents new approach immunotherapy, which can be considered simple potential method but immunologically effective development anti-MUC1

Язык: Английский

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