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JCO Precision Oncology May 2024Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.
Gong et al present two NCI-MATCH tumor-agnostic trials evaluating erdafitinib for FGFR-altered cancers, marking steppingstones in precision oncology.
Topics: Humans; Mutation; Neoplasms; Precision Medicine; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor
PubMed: 38709991
DOI: 10.1200/PO.24.00113 -
International Journal of Molecular... May 2024Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the... (Review)
Review
Bruton's Tyrosine Kinase (BTK) inhibitors have become one of the most vital drugs in the therapy of chronic lymphocytic leukemia (CLL). Inactivation of BTK disrupts the B-cell antigen receptor (BCR) signaling pathway, which leads to the inhibition of the proliferation and survival of CLL cells. BTK inhibitors (BTKi) are established as leading drugs in the treatment of both treatment-naïve (TN) and relapsed or refractory (R/R) CLL. Furthermore, BTKi demonstrate outstanding efficacy in high-risk CLL, including patients with chromosome 17p deletion, mutations, and unmutated status of the immunoglobulin heavy-chain variable region () gene. Ibrutinib is the first-in-class BTKi which has changed the treatment landscape of CLL. Over the last few years, novel, covalent (acalabrutinib, zanubrutinib), and non-covalent (pirtobrutinib) BTKi have been approved for the treatment of CLL. Unfortunately, continuous therapy with BTKi contributes to the acquisition of secondary resistance leading to clinical relapse. In recent years, it has been demonstrated that the predominant mechanisms of resistance to BTKi are mutations in or phospholipase Cγ2 (). Some differences in the mechanisms of resistance to covalent BTKi have been identified despite their similar mechanism of action. Moreover, novel mutations resulting in resistance to non-covalent BTKi have been recently suggested. This article summarizes the clinical efficacy and the latest data regarding resistance to all of the registered BTKi.
Topics: Humans; Agammaglobulinaemia Tyrosine Kinase; Leukemia, Lymphocytic, Chronic, B-Cell; Drug Resistance, Neoplasm; Protein Kinase Inhibitors; Pyrimidines; Pyrazoles; Piperidines; Adenine; Phospholipase C gamma; Antineoplastic Agents; Mutation
PubMed: 38791284
DOI: 10.3390/ijms25105246 -
Journal of Agricultural and Food... Jan 2024Fipronil, classified as a phenylpyrazole insecticide, is utilized to control agricultural, public health, and veterinary pests. Notably, its unique ecological fate... (Review)
Review
Fipronil, classified as a phenylpyrazole insecticide, is utilized to control agricultural, public health, and veterinary pests. Notably, its unique ecological fate involves degradation to toxic metabolites, which poses the risk of contamination in water and foodstuffs and potential human exposure through the food chain. In response to these concerns, there is a pressing need to develop analytical methodologies for detecting fipronil and its metabolites. This review provides a concise overview of the mode of action, metabolism, and toxicology of fipronil. Additionally, various detection strategies, encompassing antibody-based immunoassays and emerging analytical techniques, such as fluorescence assays based on aptamer/molecularly imprinted polymer/fluorescent probes, electrochemical sensors, and Raman spectroscopy, are thoroughly reviewed and discussed. The focus extends to detecting fipronil and its metabolites in crops, fruits, vegetables, animal-derived foods, water, and bodily fluids. This comprehensive exploration contributes valuable insights into the field, aiming to foster the development and innovation of more sensitive, rapid, and applicable analytical methods.
Topics: Animals; Humans; Insecticides; Pyrazoles; Immunoassay; Water
PubMed: 38252458
DOI: 10.1021/acs.jafc.3c07428 -
The Journal of Investigative Dermatology Oct 2023Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory...
Allergic contact dermatitis (ACD) and atopic dermatitis develop through delayed-type hypersensitivity reactions mediated by T cells. The development of immunomodulatory drugs, such as Jak inhibitors, would be useful for the long-term management of these diseases owing to their profile of favorable adverse effects. However, the efficacy of Jak inhibitors for ACD treatment has not been fully determined under a variety of settings. Therefore, we evaluated the effects of ruxolitinib, a Jak inhibitor for Jak1 and Jak2, using a mouse ACD model. As a result, the lower numbers of immune cells, including CD4 T cells, CD8 T cells, neutrophils, and possibly macrophages, as well as milder pathophysiological aspects have been observed in the inflamed skin of ACD with the administration of ruxolitinib. In addition, the treatment of differentiating T cells with ruxolitinib downregulated the level of IL-2-mediated glycolysis in vitro. Furthermore, symptoms of ACD did not develop in T-cell-specific Pgam1-deficient mice whose T cells had no glycolytic capacity. Taken together, our data suggest that the downregulation of glycolysis in T cells by ruxolitinib could be an important factor in the suppression of ACD development in mice.
Topics: Mice; Animals; Janus Kinase Inhibitors; CD8-Positive T-Lymphocytes; Dermatitis, Allergic Contact; Pyrazoles; Disease Models, Animal
PubMed: 37028703
DOI: 10.1016/j.jid.2023.03.1667 -
American Journal of Respiratory and... Jun 2024Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented...
Pharmacological Improvement of Cystic Fibrosis Transmembrane Conductance Regulator Function Rescues Airway Epithelial Homeostasis and Host Defense in Children with Cystic Fibrosis.
Pharmacological improvement of cystic fibrosis transmembrane conductance regulator (CFTR) function with elexacaftor/tezacaftor/ivacaftor (ETI) provides unprecedented improvements in lung function and other clinical outcomes in patients with cystic fibrosis (CF). However, ETI effects on impaired mucosal homeostasis and host defense at the molecular and cellular levels in the airways of patients with CF remain unknown. To investigate effects of ETI on the transcriptome of nasal epithelial and immune cells from children with CF at the single-cell level. Nasal swabs from 13 children with CF and at least one allele aged 6 to 11 years were collected at baseline and 3 months after initiation of ETI, subjected to single-cell RNA sequencing, and compared with swabs from 12 age-matched healthy children. Proportions of -positive cells were decreased in epithelial basal, club, and goblet cells, but not in ionocytes, from children with CF at baseline and were restored by ETI therapy to nearly healthy levels. Single-cell transcriptomics revealed an impaired IFN signaling and reduced expression of major histocompatibility complex classes I and II encoding genes in epithelial cells of children with CF at baseline, which was partially restored by ETI. In addition, ETI therapy markedly reduced the inflammatory phenotype of immune cells, particularly of neutrophils and macrophages. Pharmacological improvement of CFTR function improves innate mucosal immunity and reduces immune cell inflammatory responses in the upper airways of children with CF at the single-cell level, highlighting the potential to restore epithelial homeostasis and host defense in CF airways by early initiation of ETI therapy.
Topics: Humans; Cystic Fibrosis; Child; Cystic Fibrosis Transmembrane Conductance Regulator; Female; Male; Homeostasis; Benzodioxoles; Aminophenols; Quinolones; Indoles; Drug Combinations; Quinolines; Pyrazoles; Pyrroles; Nasal Mucosa; Pyridines
PubMed: 38259174
DOI: 10.1164/rccm.202310-1836OC -
Journal of Oncology Pharmacy Practice :... Jan 2024To provide a comprehensive review of the pharmacokinetics, pharmacodynamics, safety, and efficacy of a new Food and Drug Administration (FDA) approved Bruton's tyrosine... (Review)
Review
OBJECTIVE
To provide a comprehensive review of the pharmacokinetics, pharmacodynamics, safety, and efficacy of a new Food and Drug Administration (FDA) approved Bruton's tyrosine kinase inhibitor (BTKi), pirtobrutinib for relapsed/refractory mantle cell lymphoma (r/r MCL).
DATA SOURCES
A literature search was conducted through PubMed MEDLINE, ClinicalTrials.gov, and the FDA website (January 2018-January 2023) using the following key terms: lymphoma, non-covalent, Bruton's tyrosine kinase (BTK), and relapse. Relevant English language monographs, studies, and abstracts conducted in humans were reviewed and considered.
DATA SUMMARY
Pirtobrutinib, a novel non-covalent BTKi, was granted accelerated approval for treatment of r/r MCL on January 27th, 2023, based on an open-label, multi-center phase 1/2 BRUIN trial. In phase l, 61 patients with r/r MCL received seven dose levels of pirtobrutinib (25-300 mg). There was no reported maximum tolerated dose or dose-limiting toxicities during this study period. In phase 2, 56 r/r MCL evaluable efficacy patients received pirtobrutinib 200 mg daily. The overall response rate (ORR) was 52% (95% CI 38-65). Additionally, patients who received a previous covalent BTKi, ORR was 52% (95% CI 38-66). Neutropenia was the most common adverse reaction reported as a grade 3 or higher.
CONCLUSION
Pirtobrutinib has demonstrated safety and efficacy in heavily pre-treated adult patients with r/r MCL. Advantages of this drug include its usage in patients whose malignancy is resistant to current BTKi, tolerability, and response rate. Multiple clinical trials are underway to determine the efficacy of pirtobrutinib in other B-cell malignancies
Topics: Adult; Humans; Lymphoma, Mantle-Cell; Neoplasm Recurrence, Local; Pyrazoles; Agammaglobulinaemia Tyrosine Kinase; Protein Kinase Inhibitors
PubMed: 38043933
DOI: 10.1177/10781552231216886 -
The New England Journal of Medicine Apr 2024
Topics: Humans; Atrial Fibrillation; Pyrazoles; Pyridones; Stroke
PubMed: 38631012
DOI: 10.1056/NEJMc2401632 -
The New England Journal of Medicine Apr 2024
Topics: Humans; Atrial Fibrillation; Pyrazoles; Pyridones; Stroke
PubMed: 38631011
DOI: 10.1056/NEJMc2401632 -
Chemico-biological Interactions Aug 2024Cancer is a complex and multifaceted group of diseases with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. Dysregulation of normal... (Review)
Review
Cancer is a complex and multifaceted group of diseases with a high mortality rate characterized by uncontrolled proliferation of abnormal cells. Dysregulation of normal signalling pathways in cancer contributes to the different hallmarks of this disease. The signalling pathway of which phosphatidylinositol 3-kinase (PI3K) is a part is not an exception. In fact, dysregulated activation of PI3K signalling pathways can result in unbridled cellular proliferation and enhanced cell survival, thereby fostering the onset and advancement of cancer. Therefore, there is substantial interest in developing targeted therapies specifically aimed at inhibiting the PI3K enzyme and its associated pathways. Also, the therapeutic interest on pyrazoles and indazoles has been growing due to their various medicinal properties, namely, anticancer activity. Derivatives of these compounds have been studied as PI3K inhibitors, and they showed promising results. There are already some PI3K inhibitors approved by Food and Drug Administration (FDA), such as Idelalisib (Zydelig®) and Alpelisib (Piqray®). In this context, this review aims to address the importance of PI3K in cellular processes and its role in cancer. Additionally, it aims to report a comprehensive literature review of PI3K inhibitors, containing the pyrazole and indazole scaffolds, published in the last fifteen years, focusing on structure-activity relationship aspects, thus providing important insights for the design of novel and more effective PI3K inhibitors.
Topics: Humans; Indazoles; Pyrazoles; Neoplasms; Phosphoinositide-3 Kinase Inhibitors; Antineoplastic Agents; Protein Kinase Inhibitors; Animals; Phosphatidylinositol 3-Kinases; Phosphatidylinositol 3-Kinase; Signal Transduction
PubMed: 38823538
DOI: 10.1016/j.cbi.2024.111073 -
Bioorganic & Medicinal Chemistry Nov 2023Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are...
Staphylococcus aureus is a highly adaptable opportunistic pathogen that can form biofilms and generate persister cells, leading to life-threatening infections that are difficult to treat with antibiotics alone. Therefore, there is a need for an effective S. aureus biofilm inhibitor to combat this public health threat. In this study, a small library of indolenine-substituted pyrazoles and pyrimido[1,2-b]indazole derivatives were synthesised, of which the hit compound exhibited promising antibiofilm activities against methicillin-susceptible S. aureus (MSSA ATCC 29213) and methicillin-resistant S. aureus (MRSA ATCC 33591) at concentrations significantly lower than the planktonic growth inhibition. The hit compound could prevent biofilm formation and eradicate mature biofilms of MSSA and MRSA, with a minimum biofilm inhibitory concentration (MBIC) value as low as 1.56 µg/mL and a minimum biofilm eradication concentration (MBEC) value as low as 6.25 µg/mL. The minimum inhibitory concentration (MIC) values of the hit compound against MSSA and MRSA were 50 µg/mL and 25 µg/mL, respectively, while the minimum bactericidal concentration (MBC) values against MSSA and MRSA were > 100 µg/mL. Preliminary structure-activity relationship analysis reveals that the fused benzene ring and COOH group of the hit compound are crucial for the antibiofilm activity. Additionally, the compound was not cytotoxic to human alveolar A549 cells, thus highlighting its potential as a suitable candidate for further development as a S. aureus biofilm inhibitor.
Topics: Humans; Staphylococcus aureus; Methicillin-Resistant Staphylococcus aureus; Indazoles; Anti-Bacterial Agents; Biofilms; Staphylococcal Infections; Pyrazoles; Microbial Sensitivity Tests
PubMed: 37812886
DOI: 10.1016/j.bmc.2023.117485