scholarly journals Call for Action: Invasive Fungal Infections Associated With Ibrutinib and Other Small Molecule Kinase Inhibitors Targeting Immune Signaling Pathways

2017 ◽  
Vol 66 (1) ◽  
pp. 140-148 ◽  
Author(s):  
Georgios Chamilos ◽  
Michail S Lionakis ◽  
Dimitrios P Kontoyiannis
Keyword(s):  
Signaling Pathways ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Immune Signaling

scholarly journals Small-Molecule Protein Kinases Inhibitors and the Risk of Fungal Infections

2019 ◽  
Vol 13 (4) ◽  
pp. 229-243 ◽  
Author(s):  
Katie Bechman ◽  
James B Galloway ◽  
Kevin L Winthrop
Keyword(s):  
Protein Kinase ◽  
Tyrosine Kinase ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Fungal Infections ◽  
Break Point ◽  
Pharmacokinetic Profile ◽  
Protein Kinase Inhibitors ◽  
Janus Kinase ◽  
The Impact

Abstract Purpose of Review This review discusses fungal infections associated with licenced small-molecule protein kinase inhibitors. For each major drug class, the mechanism of action and targeted pathways and the impact on host defence against fungi are described. Recent Findings Protein kinase inhibitors are successfully used in the treatment of malignancies and immune-mediated diseases, targeting signalling pathways for a broad spectrum of cytokines and growth-stimuli. These agents predispose to fungal infections by the suppression of integral components of the adaptive and innate immune response. Summary The greatest risk of fungal infections is seen with bruton tyrosine kinase inhibitors, e.g. ibrutinib. Infections are also reported with agents that target mTOR, Janus kinase and break point cluster (Bcr) gene–Abelson (Abl) tyrosine kinase (BCR-ABL). The type of fungal infection fits mechanistically with the specific pathway targeted. Infections are often disseminated and present soon after the initiation of therapy. The pharmacokinetic profile, possibility of off-target kinase inhibition, and underlying disease pathology contribute to infection risk.

scholarly journals Antiviral Drug Screen of Kinase inhibitors Identifies Cellular Signaling Pathways Critical for SARS-CoV-2 Replication

2020 ◽  
Author(s):  
Gustavo Garcia ◽  
Arun Sharma ◽  
Arunachalam Ramaiah ◽  
Chandani Sen ◽  
Donald Kohn ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Signaling Pathways ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Cellular Signaling ◽  
Nucleoside Analogs ◽  
Protein Kinase Inhibitors ◽  
Health Crisis ◽  
Potent Antiviral Activity

ABSTRACTEmergence of a highly contagious novel coronavirus, SARS-CoV-2 that causes COVID-19, has precipitated the current global health crisis with over 479,000 deaths and more than 9.3 million confirmed cases. Currently, our knowledge of the mechanisms of COVID-19 disease pathogenesis is very limited which has hampered attempts to develop targeted antiviral strategies. Therefore, we urgently need an effective therapy for this unmet medical need. Viruses hijack and dysregulate cellular machineries in order for them to replicate and infect more cells. Thus, identifying and targeting dysregulated signaling pathways that have been taken over by viruses is one strategy for developing an effective antiviral therapy. We have developed a high-throughput drug screening system to identify potential antiviral drugs targeting SARS-CoV-2. We utilized a small molecule library of 430 protein kinase inhibitors, which are in various stages of clinical trials. Most of the tested kinase antagonists are ATP competitive inhibitors, a class of nucleoside analogs, which have been shown to have potent antiviral activity. From the primary screen, we have identified 34 compounds capable of inhibiting viral cytopathic effect in epithelial cells. Network of drug and protein relations showed that these compounds specifically targeted a limited number of cellular kinases. More importantly, we have identified mTOR-PI3K-AKT, ABL-BCR/MAPK, and DNA-Damage Response (DDR) pathways as key cellular signaling pathways critical for SARS-CoV-2 infection. Subsequently, a secondary screen confirmed compounds such as Berzosertib (VE-822), Vistusertib (AZD2014), and Nilotinib with anti SARS-CoV-2 activity. Finally, we found that Berzosertib, an ATR kinase inhibitor in the DDR pathway, demonstrated potent antiviral activity in a human epithelial cell line and human induced pluripotent stem cell (hIPSC)-derived cardiomyocytes. These inhibitors are already in clinical trials of phase 2 or 3 for cancer treatment, and can be repurposed as promising drug candidates for a host-directed therapy of SARS-CoV-2 infection. In conclusion, we have identified small molecule inhibitors exhibiting anti SARS-CoV-2 activity by blocking key cellular kinases, which gives insight on important mechanism of host-pathogen interaction. These compounds can be further evaluated for the treatment of COVID-19 patients following additional in vivo safety and efficacy studies.DisclosuresNone declared.

scholarly journals The Zebrafish as a Model Host for Invasive Fungal Infections

2018 ◽  
Vol 4 (4) ◽  
pp. 136 ◽  
Author(s):  
Emily Rosowski ◽  
Benjamin Knox ◽  
Linda Archambault ◽  
Anna Huttenlocher ◽  
Nancy Keller ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Fungal Infection ◽  
Small Molecule ◽  
In Vivo Imaging ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Small Molecule Screening

The zebrafish has become a widely accepted model host for studies of infectious disease, including fungal infections. The species is genetically tractable, and the larvae are transparent and amenable to prolonged in vivo imaging and small molecule screening. The aim of this review is to provide a thorough introduction into the published studies of fungal infection in the zebrafish and the specific ways in which this model has benefited the field. In doing so, we hope to provide potential new zebrafish researchers with a snapshot of the current toolbox and prior results, while illustrating how the model has been used well and where the unfulfilled potential of this model can be found.

scholarly journals The infectious thyroid nodule: a case report of mucormycosis associated with ibrutinib therapy

2019 ◽  
Vol 48 (1) ◽  
Author(s):  
Marco A. Mascarella ◽  
Lorne Schweitzer ◽  
Mahmoud Alreefi ◽  
Jennifer Silver ◽  
Derin Caglar ◽  
...  
Keyword(s):  
Thyroid Nodule ◽  
Head And Neck ◽  
Needle Biopsy ◽  
Kinase Inhibitors ◽  
Fungal Infections ◽  
Invasive Fungal Infections ◽  
Lymphocytic Leukemia ◽  
Case Presentation ◽  
Life Threatening

Abstract Background Acute invasive fungal infections of the head and neck secondary to tyrosine kinase inhibitors are rare and potentially life-threatening events. Case presentation We report a case of mucormycosis of the thyroid gland in a patient known for chronic lymphocytic leukemia receiving ibrutinib who presented with a rapidly growing thyroid nodule and dysphonia. An acute invasive fungal infection was identified on a core needle biopsy; mucormycosis was confirmed on culture. The patient was successfully treated with surgical debridement and long-term antifungal therapy. Conclusion Patients on ibrutinib may be at risk of acute invasive fungal infections of the head and neck.

scholarly journals Fungal Infections with Ibrutinib and Other Small-Molecule Kinase Inhibitors

2019 ◽  
Vol 13 (3) ◽  
pp. 86-98 ◽  
Author(s):  
Marissa A. Zarakas ◽  
Jigar V. Desai ◽  
Georgios Chamilos ◽  
Michail S. Lionakis
Keyword(s):  
Small Molecule ◽  
Kinase Inhibitors ◽  
Fungal Infections
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