Your browser doesn't support javascript.
Show: 20 | 50 | 100
Results 1 - 10 de 10
Filter
1.
Cells ; 10(9)2021 08 31.
Article in English | MEDLINE | ID: covidwho-1390542

ABSTRACT

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes ß-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived ß-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing ß-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human ß-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.


Subject(s)
Homeostasis , Insulin-Secreting Cells/cytology , Insulin-Secreting Cells/enzymology , Insulin/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Genes, Reporter , Harmine/pharmacology , Homeostasis/drug effects , Humans , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Insulin-Secreting Cells/drug effects , Kinetics , Male , Mice , Models, Biological , NFATC Transcription Factors/metabolism , Organoids/drug effects , Organoids/metabolism , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/metabolism , Rats , Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/metabolism
2.
Int J Mol Sci ; 22(14)2021 Jul 16.
Article in English | MEDLINE | ID: covidwho-1389404

ABSTRACT

In the past few years, Bruton's tyrosine Kinase (Btk) has emerged as new target in medicinal chemistry. Since approval of ibrutinib in 2013 for treatment of different hematological cancers (as leukemias and lymphomas), two other irreversible Btk inhibitors have been launched on the market. In the attempt to overcome irreversible Btk inhibitor limitations, reversible compounds have been developed and are currently under evaluation. In recent years, many Btk inhibitors have been patented and reported in the literature. In this review, we summarized the (ir)reversible Btk inhibitors recently developed and studied clinical trials and preclinical investigations for malignancies, chronic inflammation conditions and SARS-CoV-2 infection, covering advances in the field of medicinal chemistry. Furthermore, the nanoformulations studied to increase ibrutinib bioavailability are reported.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Adenine/administration & dosage , Adenine/analogs & derivatives , Agammaglobulinaemia Tyrosine Kinase/metabolism , COVID-19/drug therapy , Chemistry, Pharmaceutical/methods , Drug Delivery Systems/methods , Hematologic Neoplasms/drug therapy , Humans , Inflammation/drug therapy , Neoplasms/drug therapy , Piperidines/administration & dosage , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/administration & dosage , SARS-CoV-2/drug effects
3.
Int Immunopharmacol ; 99: 108012, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1330894

ABSTRACT

ALK targeting with tyrosine kinase inhibitors (TKIs) is a highly potent treatment option for the therapy of ALK positive non-small cell lung cancer (NSCLC). However, pharmacokinetics of TKIs leads to clinically significant drug interactions, and the interfering co-medication may hamper the anti-cancer therapeutic management. Here, we present for the first time a drug interaction profile of ALK-TKIs, crizotinib and alectinib, and immunosuppressive agent cyclosporine A in kidney transplant recipients diagnosed with ALK+ lung cancer. Based on therapeutic drug monitoring of cyclosporin A plasma level, the dose of cyclosporine A has been adjusted to achieve a safe and effective therapeutic level in terms of both cancer treatment and kidney transplant condition. Particularly, 15 years upon the kidney transplantation, the stage IV lung cancer patient was treated with the 1st-line chemotherapy, the 2nd-line ALK-TKI crizotinib followed by ALK-TKI alectinib. The successful therapy with ALK-TKIs has been continuing for more than 36 months, including the period when the patient was treated for COVID-19 bilateral pneumonia. Hence, the therapy of ALK+ NSCLC with ALK-TKIs in organ transplant recipients treated with cyclosporine A may be feasible and effective.


Subject(s)
Anaplastic Lymphoma Kinase/antagonists & inhibitors , Carbazoles/pharmacology , Carcinoma, Non-Small-Cell Lung/drug therapy , Crizotinib/pharmacology , Lung Neoplasms/drug therapy , Piperidines/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Carcinoma, Non-Small-Cell Lung/pathology , Carcinoma, Non-Small-Cell Lung/secondary , Drug Interactions , Humans , Kidney Transplantation , Lung Neoplasms/pathology , Male , Middle Aged , Protein Kinase Inhibitors/pharmacology
4.
J Leukoc Biol ; 109(1): 49-53, 2021 01.
Article in English | MEDLINE | ID: covidwho-1188016

ABSTRACT

Bruton's tyrosine kinase (BTK) signaling is involved in innate immune responses and regulates the production of proinflammatory cytokines that can contribute to COVID-19 immunopathology. Clinical trials with BTK inhibitors in COVID-19 treatment have been proposed, and previous studies have attempted to investigate the therapeutic effects of ibrutinib and underlying mechanisms in treating viral pneumonia. These attempts, however, did not consider potential off target effect of BTK inhibitors on T cell differentiation, function, and survival, which may be beneficial in treatment for COVID-19. Here, we summarize the current knowledge of BTK/IL-2-inducible T-cell kinase (ITK) signaling in immunopathology and lymphopenia and discuss the potential of BTK/ITK dual inhibitors such as ibrutinib in modulating immunopathology and lymphopenia, for COVID-19 therapy.


Subject(s)
Agammaglobulinaemia Tyrosine Kinase , COVID-19/drug therapy , Lymphopenia , SARS-CoV-2 , Signal Transduction , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/immunology , Agammaglobulinaemia Tyrosine Kinase/metabolism , COVID-19/enzymology , COVID-19/immunology , Cytokines/immunology , Humans , Immunity, Innate/drug effects , Lymphopenia/drug therapy , Lymphopenia/enzymology , Lymphopenia/immunology , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/immunology , Protein-Tyrosine Kinases/metabolism , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology
5.
Molecules ; 25(11)2020 Jun 11.
Article in English | MEDLINE | ID: covidwho-981163

ABSTRACT

Flavonoids are widely used as phytomedicines. Here, we report on flavonoid phytomedicines with potential for development into prophylactics or therapeutics against coronavirus disease 2019 (COVID-19). These flavonoid-based phytomedicines include: caflanone, Equivir, hesperetin, myricetin, and Linebacker. Our in silico studies show that these flavonoid-based molecules can bind with high affinity to the spike protein, helicase, and protease sites on the ACE2 receptor used by the severe acute respiratory syndrome coronavirus 2 to infect cells and cause COVID-19. Meanwhile, in vitro studies show potential of caflanone to inhibit virus entry factors including, ABL-2, cathepsin L, cytokines (IL-1ß, IL-6, IL-8, Mip-1α, TNF-α), and PI4Kiiiß as well as AXL-2, which facilitates mother-to-fetus transmission of coronavirus. The potential for the use of smart drug delivery technologies like nanoparticle drones loaded with these phytomedicines to overcome bioavailability limitations and improve therapeutic efficacy are discussed.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus OC43, Human/drug effects , Flavonoids/pharmacology , Peptidyl-Dipeptidase A/chemistry , Pneumonia, Viral/drug therapy , Spike Glycoprotein, Coronavirus/chemistry , Angiotensin-Converting Enzyme 2 , Animals , Antiviral Agents/chemistry , Betacoronavirus/chemistry , Betacoronavirus/growth & development , Binding Sites , COVID-19 , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/genetics , Coronavirus OC43, Human/chemistry , Coronavirus OC43, Human/growth & development , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Flavonoids/chemistry , Humans , Interleukins/antagonists & inhibitors , Interleukins/chemistry , Interleukins/genetics , Interleukins/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/virology , Lung/drug effects , Lung/pathology , Lung/virology , Mice , Molecular Docking Simulation , Nanoparticles/administration & dosage , Nanoparticles/chemistry , Pandemics , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Phytotherapy/methods , Pneumonia, Viral/genetics , Primary Cell Culture , Protein Binding , Protein Interaction Domains and Motifs , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/metabolism , Thermodynamics , Virus Internalization/drug effects
6.
Basic Clin Pharmacol Toxicol ; 128(4): 621-624, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-965811

ABSTRACT

Since the emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) at the end of 2019, no vaccine has been approved to counter this infection and the available treatments are mainly directed against the immune pathology caused by the infection. The coronavirus disease 2019 (COVID-19) is currently causing a worldwide pandemic, pointing the urgent need for effective treatment. In such emergency, drug repurposing presents the best option for a rapid antiviral response. We assess here the in vitro activity of nilotinib, imatinib and dasatinib, three Abl tyrosine kinase inhibitors, against SARS-CoV-2. Although the last two compounds do not show antiviral efficacy, we observe inhibition with nilotinib in Vero-E6 cells and Calu-3 cells with EC50s of 1.44 µM and 3.06 µM, respectively. These values are close to the mean peak concentration of nilotinib observed at steady state in serum, making this compound a potential candidate for treatment of COVID-19 in vivo.


Subject(s)
Antiviral Agents/pharmacology , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrimidines/pharmacology , SARS-CoV-2/drug effects , Animals , Cell Line , Chlorocebus aethiops , Dasatinib/pharmacology , Dose-Response Relationship, Drug , Humans , Imatinib Mesylate/pharmacology , In Vitro Techniques , Vero Cells/virology
7.
Endocrine ; 70(1): 6-10, 2020 10.
Article in English | MEDLINE | ID: covidwho-654265

ABSTRACT

Primary neuroendocrine tumors of the thymus are extremely rare. In patients with advanced disease, tumor growth control, and sometimes also syndrome control are the main goals of systemic therapy. Unfortunately, no standard therapies are available in clinical practice; therefore, clinical studies are strongly recommended. Axitinib (AXI) is a tyrosine kinase inhibitor, currently under investigation in an international phase II/III trial including thymic neuroendocrine tumors. Over the past 5 months, the entire world has been facing a devastating medical emergency brought about by a pandemic due to a novel coronavirus known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which emerged in Wuhan, China, in late 2019. Since then, health professionals have been expending all their efforts on trying to provide the best available treatments for patients involved. Patients with cancer, especially those with thoracic involvement, are at higher risk of coronavirus disease 19 (COVID-19) and its complications because of their immunosuppressive status caused by the cancer and the anticancer therapies. As it remains unclear how to optimally manage such patients, we wished to report our experience with a patient with a metastatic neuroendocrine tumor of the thymus infected with SARS-CoV-2 in the hope that it may provide some insights and reflections on the management of cancer patients during this challenging time in our history.


Subject(s)
Betacoronavirus , Carcinoid Tumor/drug therapy , Coronavirus Infections/epidemiology , Neuroendocrine Tumors/drug therapy , Pneumonia, Viral/epidemiology , Thymus Neoplasms/drug therapy , Aged , Axitinib/adverse effects , Axitinib/therapeutic use , Azithromycin/therapeutic use , COVID-19 , Carcinoid Tumor/epidemiology , Comorbidity , Coronavirus Infections/diagnosis , Humans , Hydroxychloroquine/therapeutic use , Italy/epidemiology , Male , Neuroendocrine Tumors/epidemiology , Pandemics , Pneumonia, Viral/diagnosis , Protein-Tyrosine Kinases/antagonists & inhibitors , Randomized Controlled Trials as Topic , SARS-CoV-2 , Thymus Neoplasms/epidemiology , Tomography, X-Ray Computed , Treatment Outcome
9.
Ann Hematol ; 99(8): 1701-1707, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-613171

ABSTRACT

COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.


Subject(s)
Betacoronavirus , Complement Inactivating Agents/administration & dosage , Coronavirus Infections/metabolism , Drug Delivery Systems/methods , Endothelium, Vascular/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Pneumonia, Viral/metabolism , Protein-Tyrosine Kinases/metabolism , Antibodies, Monoclonal, Humanized/administration & dosage , COVID-19 , Clinical Trials, Phase II as Topic/methods , Coronavirus Infections/drug therapy , Coronavirus Infections/pathology , Endothelium, Vascular/drug effects , Endothelium, Vascular/pathology , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Imatinib Mesylate/administration & dosage , Pandemics/prevention & control , Pneumonia, Viral/drug therapy , Pneumonia, Viral/pathology , Protein-Tyrosine Kinases/antagonists & inhibitors , SARS-CoV-2 , Signal Transduction/drug effects , Signal Transduction/physiology
SELECTION OF CITATIONS
SEARCH DETAIL