Lysine demethylase 5B (KDM5B) is a member of the Jumonji AT-rich interactive domain 1 family. Its main function is to demethylate di/trimethyl histone H3 lysine 4 and it plays a crucial role in the occurrence and development of cancer. In this study, we performed structure-based optimization of KDM5B inhibitors based on our previous work and the most active compound we synthesized was 11ad. Molecular modeling studies and thermal shift assays revealed that 11ad specifically targets KDM5B at the molecular and cellular levels. Crucially, 11ad demonstrated good pharmacokinetic properties and anti-prostate cancer activity in a xenograft model. Furthermore, unexpectedly, the specificity of 11ad for prostate cancer was found to be related to its inhibition of the phosphoinositide 3-kinase/AKT pathway. This is the first report of a KDM5B inhibitor affecting this pathway. Taken together, our findings indicate that 11ad is a novel KDM5B inhibitor that may serve as a lead compound for the development of treatments for prostate cancer.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.ejmech.2023.115250 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
functional validation of anti-CD19 chimeric antigen receptor T cells expressing lysine-specific demethylase 1 short hairpin RNA for the treatment of diffuse large B cell lymphoma.
Front Immunol
January 2025
Institute of Infection, Immunology and Tumor Microenvironment, Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, China.
Background: Chimeric antigen receptor T (CAR-T) cell therapy is more effective in relapsed or refractory diffuse large B cell lymphoma (DLBCL) than other therapies, but a high proportion of patients relapse after CAR-T cell therapy owing to antigen escape, limited persistence of CAR-T cells, and immunosuppression in the tumor microenvironment. CAR-T cell exhaustion is a major cause of relapse. Epigenetic modifications can regulate T cell activation, maturation and depletion; they can be applied to reduce T cell depletion, improve infiltration, and promote memory phenotype formation to reduce relapse after CAR-T cell therapy.
View Article and Find Full Text PDFDual targeting PPARα and NPC1L1 metabolic vulnerabilities blocks tumorigenesis.
Cancer Lett
January 2025
Advanced Medical Research Institute, Qilu College of Medicine, Shandong University, Jinan, 250012, China. Electronic address:
Dysregulated lipid metabolism is linked to tumor progression. In this study, we identified Niemann-Pick C1-like 1 (NPC1L1) as a downstream effector of PKM2. In breast cancer cells, PKM2 knockout (KO) enhanced NPC1L1 expression while downregulating peroxisome proliferator-activated receptor α (PPARα) signaling pathway.
View Article and Find Full Text PDFHomocysteine Metabolites, Endothelial Dysfunction, and Cardiovascular Disease.
Int J Mol Sci
January 2025
Department of Biochemistry and Biotechnology, Poznań University of Life Sciences, 60-632 Poznań, Poland.
Atherosclerosis is accompanied by inflammation that underlies cardiovascular disease (CVD) and its vascular manifestations, including acute stroke, myocardial infarction, and peripheral artery disease, the leading causes of morbidity/mortality worldwide. The monolayer of endothelial cells formed on the luminal surface of arteries and veins regulates vascular tone and permeability, which supports vascular homeostasis. Endothelial dysfunction, the first step in the development of atherosclerosis, is caused by mechanical and biochemical factors that disrupt vascular homeostasis and induce inflammation.
View Article and Find Full Text PDFMarek's disease virus-encoded microRNA-M6-5p facilitates viral latent infection by targeting histone demethylase KDM2B.
J Virol
January 2025
Institute of Animal Husbandry and Veterinary Medicine, Beijing Academy of Agriculture and Forestry Sciences, Beijing, China.
Marek's disease virus (MDV), a highly contagious and oncogenic avian alphaherpesvirus, establishes a latent infection primarily in CD4 T cells. Latent infections are necessary for both persistent lifelong MDV infection and viral tumorigenesis. MicroRNAs (miRNAs) play critical roles as post-transcriptional regulators of viral infections.
View Article and Find Full Text PDFDevelopment of BACE2-IN-1/tranylcypromine-based compounds to induce steroidogenesis-dependent neuroprotection.
Biomed Pharmacother
January 2025
Ph.D. Program in Medical Neuroscience, Taipei Medical University and National Health Research Institutes, Taipei 11031, Taiwan; TMU Research Center for Drug Discovery, Taipei Medical University, Taipei 11031, Taiwan; International Master Program in Medical Neuroscience, Taipei Medical University, New Taipei City 23564, Taiwan; TMU Research Center of Neuroscience, Taipei Medical University, Taipei 11031, Taiwan; Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung 80780, Taiwan. Electronic address:
Traumatic brain injury (TBI) constitutes a significant burden on global healthcare systems, especially affecting younger populations, where it is a leading cause of disability and mortality. Current treatments for TBI mainly focus on preventing further brain damage and controlling symptoms. However, despite these approaches, several clinical needs remain unmet.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!