Chemical agonism of human caseinolytic protease P (HsClpP) is increasingly being recognized as a potential anticancer strategy due to its critical role in maintaining mitochondrial homeostasis. We unveil the discovery of 5-(piperidin-4-yl)-1,2,4-oxadiazole derivatives as a novel class of HsClpP agonists and demonstrate for the first time the application of HsClpP agonists in the treatment of hepatocellular carcinoma (HCC) (Pace, A.; Pierro, P. The new era of 1,2,4-oxadiazoles. . 2009, 7 (21), 4337-4348). Compound exhibited potent HsClpP agonistic activity in the α-casein hydrolysis assay (EC = 1.30 μM) and inhibited the proliferation of HCCLM3 cells (IC = 3.1 μM, 21.4-fold higher than hit ADX-47273). Mechanistically, induces degradation of respiratory chain complex subunits and leads to apoptosis in HCC cells. results demonstrated that has potent tumor growth inhibitory activity and has a superior safety profile compared to the kinase inhibitor sorafenib. Overall, we developed a novel class of HsClpP agonists that can potentially be used for the treatment of HCC.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/acs.jmedchem.4c00080 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Signaling Dynamics in Osteogenesis: Unraveling Therapeutic Targets for Bone Generation.
Curr Drug Targets
January 2025
Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, FL33458, United States.
Diseases affecting bone encompass a spectrum of disorders, from prevalent conditions such as osteoporosis and Paget's disease, collectively impacting millions, to rare genetic disorders including Fibrodysplasia Ossificans Progressiva (FOP). While several classes of drugs, such as bisphosphonates, synthetic hormones, and antibodies, are utilized in the treatment of bone diseases, their efficacy is often curtailed by issues of tolerability and high incidence of adverse effects. Developing therapeutic agents for bone diseases is hampered by the fact that numerous pathways regulating bone metabolism also perform pivotal functions in other organ systems.
View Article and Find Full Text PDFResults from a UK consensus about the optimal prescribing of medium strength triple therapy in uncontrolled adult asthma patients in the NHS.
J Family Med Prim Care
December 2024
Medicines Evaluation Unit, Manchester University National Health Service Foundation Trust, University of Manchester, Manchester, United Kingdom.
Context: An inhaled corticosteroid (ICS) in combination with a long-acting β2-agonist (LABA) is a common treatment approach for asthma patients not controlled on ICS alone, but a significant proportion of patients remain uncontrolled on this combination and treatment adherence can also be a challenge. One of the options for adults whose asthma is uncontrolled in an ICS/LABA is the addition of a long-acting muscarinic receptor antagonist (LAMA), an approach commonly referred to as 'triple therapy'. The use of medium-strength ICS/LABA/LAMA is established in treating chronic obstructive pulmonary disease but is less well-established in asthma.
View Article and Find Full Text PDFHistone deacetylase 6 inhibition prevents hypercholesterolemia-induced erectile dysfunction independent of changes in markers of autophagy.
Sex Med
December 2024
Department of Health, Nutrition, and Food Sciences, Florida State University, Tallahassee, FL 32306, United States.
Background: Erectile dysfunction is a condition with a rapidly increasing prevalence globally with a strong correlation to the increase in obesity and cardiovascular disease rates.
Aim: The aim of the current study is to investigate the potential role of tubacin, a histone deacetylase 6 (HDAC6) inhibitor, in restoring erectile function in a hypercholesterolemia-induced endothelial dysfunction model.
Methods: Thirty-nine male C57Bl/6 J mice were divided into 3 groups.
Aims: To assess the renoprotective effects of dulaglutide and identify mechanisms of action in patients with type 2 diabetes and diabetic kidney disease (DKD).
Materials And Methods: Outpatients/ambulant patients at the Department of Endocrinology, Affiliated Hospital of Xuzhou Medical University between October 2021 and July 2023, with type 2 diabetes and DKD, a urinary albumin-to-creatinine ratio (UACR) ≥ 3 mg/mmol and who were receiving hypoglycemic agents were prescribed dulaglutide at a dose rate of 0.75 - 1.
Real-world retrospective study in elderly patients aged 65 years and older with type 2 diabetes mellitus treated with daily oral semaglutide (SEMA-elderly).
Diabetes Obes Metab
January 2025
UOSD Diabetologia Endocrinologia, ASL RM5, Rome, Italy.
Aim: This real-world, retrospective cohort study aimed to assess the efficacy, safety and tolerability of oral semaglutide-the first GLP-1 receptor agonist available in oral form-in patients aged 65 years and older with type 2 diabetes mellitus (T2DM).
Materials And Methods: The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline (V1) to six months (V3). Secondary endpoints included change in body weight, proportion of patients achieving HbA1c <7%, proportion of patients achieving both an HbA1c reduction of ≥1% and a body weight reduction of ≥5%.
Want 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!