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International Journal of Molecular... Dec 2023The development of a wider range of therapeutic options is a key objective in drug discovery for chronic obstructive pulmonary disease (COPD). Fundamental advances in... (Review)
Review
The development of a wider range of therapeutic options is a key objective in drug discovery for chronic obstructive pulmonary disease (COPD). Fundamental advances in lung biology have the potential to greatly expand the number of therapeutic targets in COPD. The recently reported successful Phase 3 clinical trial of the first biologic agent for COPD, the monoclonal antibody dupilumab, adds additional support to the importance of targeting inflammatory pathways in COPD. However, numerous other cellular mechanisms are important targets in COPD therapeutics, including airway remodeling, the CFTR ion channel, and mucociliary function. Some of these emerging targets can be exploited by the expanded use of existing COPD drugs, such as roflumilast, while targeting others will require the development of novel molecular entities. The identification of additional therapeutic targets and agents has the potential to greatly expand the value of using clinical and biomarker data to classify COPD into specific subsets, each of which can be predictive of an enhanced response to specific subset(s) of targeted therapies. The author reviews established and emerging drug targets in COPD and uses this as a framework to define a novel classification of COPD based on therapeutic targets. This novel classification has the potential to enhance precision medicine in COPD patient care and to accelerate clinical trials and pre-clinical drug discovery efforts.
Topics: Humans; Precision Medicine; Pulmonary Disease, Chronic Obstructive; Lung; Inflammation; Aminopyridines; Cyclopropanes; Ion Channels
PubMed: 38139192
DOI: 10.3390/ijms242417363 -
JAMA Sep 2022
Topics: Aminopyridines; Benzamides; Cyclopropanes; Humans; Phosphodiesterase 4 Inhibitors; Psoriasis
PubMed: 36125485
DOI: 10.1001/jama.2022.14663 -
The Lancet. Oncology Jun 2022
Topics: Aminopyridines; Benzimidazoles; Humans; Mesothelioma, Malignant
PubMed: 35654054
DOI: 10.1016/S1470-2045(22)00276-5 -
Drugs Jun 2021Fostamatinib (Tavalisse; Tavlesse) is the first spleen tyrosine kinase (Syk) inhibitor approved for the treatment of chronic immune thrombocytopenia (ITP) in adult... (Review)
Review
Fostamatinib (Tavalisse; Tavlesse) is the first spleen tyrosine kinase (Syk) inhibitor approved for the treatment of chronic immune thrombocytopenia (ITP) in adult patients who have had an insufficient response to previous treatment. By inhibiting Syk activation in macrophages, fostamatinib blocks autoantibody-mediated platelet phagocytosis. In the placebo-controlled phase III FIT1 and FIT2 trials, 24 weeks of oral fostamatinib therapy increased platelet count in previously treated adults with ITP. A significantly higher proportion of patients achieved stable response with fostamatinib than with placebo in FIT1, but not in FIT2; however, pooled analyses of the two studies showed that fostamatinib produced significantly higher stable and overall response rates than placebo. Interim findings from the ongoing FIT3 open-label extension study suggested that the efficacy of fostamatinib was maintained with long-term treatment (up to 62 months; median duration 6 months), including in patients receiving fostamatinib as second- or later-line treatment. Fostamatinib had a generally manageable tolerability profile in all three FIT studies, with no serious safety risks. Fostamatinib therefore provides an alternative treatment option for chronic ITP in adult patients with an insufficient response to previous treatment.
Topics: Aminopyridines; Chronic Disease; Clinical Trials, Phase III as Topic; Humans; Morpholines; Purpura, Thrombocytopenic, Idiopathic; Pyrimidines; Randomized Controlled Trials as Topic; Syk Kinase
PubMed: 33970459
DOI: 10.1007/s40265-021-01524-y -
Scientific Reports May 2023F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention...
F508del, the most frequent mutation in cystic fibrosis (CF), impairs the stability and folding of the CFTR chloride channel, thus resulting in intracellular retention and CFTR degradation. The F508del defect can be targeted with pharmacological correctors, such as VX-809 and VX-445, that stabilize CFTR and improve its trafficking to plasma membrane. Using a functional test to evaluate a panel of chemical compounds, we have identified tricyclic pyrrolo-quinolines as novel F508del correctors with high efficacy on primary airway epithelial cells from CF patients. The most effective compound, PP028, showed synergy when combined with VX-809 and VX-661 but not with VX-445. By testing the ability of correctors to stabilize CFTR fragments of different length, we found that VX-809 is effective on the amino-terminal portion of the protein that includes the first membrane-spanning domain (amino acids 1-387). Instead, PP028 and VX-445 only show a stabilizing effect when the second membrane-spanning domain is included (amino acids 1-1181). Our results indicate that tricyclic pyrrolo-quinolines are a novel class of CFTR correctors that, similarly to VX-445, interact with CFTR at a site different from that of VX-809. Tricyclic pirrolo-quinolines may represent novel CFTR correctors suitable for combinatorial pharmacological treatments to treat the basic defect in CF.
Topics: Humans; Cystic Fibrosis Transmembrane Conductance Regulator; Chloride Channels; Quinolines; Cystic Fibrosis; Benzodioxoles; Aminopyridines; Mutation
PubMed: 37165082
DOI: 10.1038/s41598-023-34440-0 -
ACS Chemical Biology Oct 2020Interleukin-4 (IL-4) is a multifunctional cytokine and an important regulator of inflammation. When deregulated, IL-4 activity is associated with asthma, allergic...
Interleukin-4 (IL-4) is a multifunctional cytokine and an important regulator of inflammation. When deregulated, IL-4 activity is associated with asthma, allergic inflammation, and multiple types of cancer. While antibody-based inhibitors targeting the soluble cytokine have been evaluated clinically, they failed to achieve their end points in trials. Small-molecule inhibitors are an attractive alternative, but identifying effective chemotypes that inhibit the protein-protein interactions between cytokines and their receptors remains an active area of research. As a result, no small-molecule inhibitors to the soluble IL-4 cytokine have yet been reported. Here, we describe the first IL-4 small-molecule inhibitor identified and characterized through a combination of binding-based approaches and cell-based activity assays. The compound features a nicotinonitrile scaffold with micromolar affinity and potency for the cytokine and disrupts type II IL-4 signaling in cells. Small-molecule inhibitors of these important cell-signaling proteins have implications for numerous immune-related disorders and inform future drug discovery and design efforts for these challenging protein targets.
Topics: Aminopyridines; Humans; Interleukin-4; Ligands; Phosphorylation; Protein Binding; STAT6 Transcription Factor; Signal Transduction; Small Molecule Libraries; THP-1 Cells
PubMed: 32902255
DOI: 10.1021/acschembio.0c00615 -
Drugs May 2017Ribociclib is an oral, small-molecule inhibitor of cyclin-dependent kinase (CDK) 4 and 6 that is under development by Novartis for the treatment of cancer. CDKs play an...
Ribociclib is an oral, small-molecule inhibitor of cyclin-dependent kinase (CDK) 4 and 6 that is under development by Novartis for the treatment of cancer. CDKs play an important role in cell cycle progression and cellular proliferation, and inhibition of these kinases with ribociclib results in G1 phase cell-cycle arrest. Ribociclib, in combination with an aromatase inhibitor, was recently approved in the USA for the first-line treatment of advanced breast cancer and has been submitted for approval in the EU for this indication. Ribociclib is undergoing further phase III investigations in breast cancer and is being evaluated in phase I or II trials for various solid tumour types and haematological malignancies. This article summarizes the milestones in the development of ribociclib leading to this first global approval for use as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced or metastatic breast cancer.
Topics: Administration, Oral; Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Clinical Trials as Topic; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Drug Approval; Enzyme Inhibitors; Female; Humans; Purines; United States; United States Food and Drug Administration
PubMed: 28417244
DOI: 10.1007/s40265-017-0742-0 -
Psychopharmacology Apr 2023Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects.
RATIONALE
Drug combinations are commonly used in pain management, which can produce potent analgesic effects with reduced dosage and adverse effects.
OBJECTIVE
This study was designed to evaluate the anti-nociceptive effects and adverse effects of new combinations of flupirtine (a Kv7 potassium channel opener) and antihistamines (promethazine, fexofenadine) on acute and chronic pain in mice, and the possible mechanisms behind the synergistic analgesic effects were preliminarily investigated.
METHODS
In acetic acid writhing test, carrageenan-induced inflammatory pain model, and paclitaxel-induced neuropathic pain model, the interaction indexes (γ) between flupirtine and antihistamines were determined by isobolographic analysis. Furthermore, the Kv7 channel blocker XE991 was used to determine whether the effects of single agents and drug combinations on paclitaxel- and carrageenan-induced mechanical allodynia were mediated by Kv7 channels. Finally, hepatotoxicity markers, liver histopathology, and the rotarod test were used to investigate the adverse effects of drugs in combination doses.
RESULTS
The interaction indexes of flupirtine-promethazine and flupirtine-fexofenadine in all the above three pain models were lower than 1. The analgesic effects of flupirtine (13 mg/kg), promethazine (5 mg/kg), fexofenadine (20 mg/kg), and their combinations were antagonized significantly by XE991 (3 mg/kg). And the adverse effects of flupirtine and antihistamines in combination doses were not significantly different from the vehicle group.
CONCLUSIONS
Flupirtine and antihistamines produced synergistic analgesic effects in all the above pain models. The analgesic effects of antihistamines were partially mediated by Kv7/M channels, and the activation of Kv7/M channels may be partly responsible for the synergistic analgesic effects between flupirtine and antihistamines.
Topics: Mice; Animals; Analgesics; Promethazine; Carrageenan; Aminopyridines; Neuralgia; Histamine Antagonists
PubMed: 36752814
DOI: 10.1007/s00213-023-06329-3 -
Disruption of mitochondrial oxidative phosphorylation by chidamide eradicates leukemic cells in AML.Clinical & Translational Oncology :... Jun 2023Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting...
PURPOSE
Nowadays, the oxidative phosphorylation (OXPHOS) correlated with leukemogenesis and treatment response is extensive. Thus, exploration of novel approaches in disrupting OXPHOS in AML is urgently needed.
MATERIALS AND METHODS
Bioinformatical analysis of TCGA AML dataset was performed to identify the molecular signaling of OXPHOS. The OXPHOS level was measured through a Seahorse XFe96 cell metabolic analyzer. Flow cytometry was applied to measure mitochondrial status. Real-time qPCR and western blot were used to analyze the expression of mitochondrial or inflammatory factors. MLL-AF9-induced leukemic mice were conducted to measure the anti-leukemia effect of chidamide.
RESULTS
Here, we reported that AML patients with high OXPHOS level were in a poor prognosis, which was associated with high expression of HDAC1/3 (TCGA). Inhibition of HDAC1/3 by chidamide inhibited cell proliferation and induced apoptotic cell death in AML cells. Intriguingly, chidamide could disrupt mitochondrial OXPHOS as assessed by inducing mitochondrial superoxide and reducing oxygen consumption rate, as well as decreasing mitochondrial ATP production. We also observed that chidamide augmented HK1 expression, while glycolysis inhibitor 2-DG could reduce the elevation of HK1 and improve the sensitivity of AML cells exposed to chidamide. Furthermore, HDAC3 was correlated with hyperinflammatory status, while chidamide could downregulate the inflammatory signaling in AML. Notably, chidamide eradicated leukemic cells in vivo and prolonged the survival time of MLL-AF9-induced AML mice.
CONCLUSION
Chidamide disrupted mitochondrial OXPHOS, promoted cell apoptosis and reduced inflammation in AML cells. These findings exhibited a novel mechanism that targeting OXPHOS would be a novel strategy for AML treatment.
Topics: Animals; Mice; Leukemia, Myeloid, Acute; Oxidative Phosphorylation; Aminopyridines; Benzamides; Apoptosis; Cell Line, Tumor
PubMed: 36899123
DOI: 10.1007/s12094-023-03079-8 -
Expert Opinion on Drug Safety Jul 2019: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations,... (Review)
Review
: Activation of phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathways occurs in 70% of breast cancer, including PIK3CA activating mutations, PTEN loss and AKT mutation. It is associated with poor prognosis and resistance to anti-HER2 and endocrine therapy. PI3K inhibitors are promising anticancer targets that can reverse resistance to these therapies. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different solid tumors as monotherapy or in combination. : This article reviews preclinical data, clinical studies that have evaluated the efficacy and safety profiles of buparlisib as a monotherapy or in combination with targeted therapy (including endocrine and anti-HER2 therapy) or cytotoxics. The authors cover completed and ongoing studies to evaluate the benefit vs risk profile of buparlisib. : Targeting PI3K showed efficacy in BC. Buparlisib, a pan PI3K inhibitor, presents manageable but not negligible toxicity with an activity/toxicity ratio in favor of the use of emerging second generation, α-selective PI3K inhibitors for ongoing and future trials.
Topics: Administration, Oral; Aminopyridines; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Molecular Targeted Therapy; Morpholines; Mutation; Phosphoinositide-3 Kinase Inhibitors
PubMed: 31159599
DOI: 10.1080/14740338.2019.1623877