scholarly journals Observations on the use of Bruton’s tyrosine kinase inhibitors in SAR-CoV-2 and cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Brooke Benner ◽  
William E. Carson
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Innate Immune ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Process Understanding ◽  
Btk Inhibitors ◽  
Severe Lung Disease ◽  
Pro Inflammatory Cytokines ◽  
Severe Lung

AbstractBruton’s tyrosine kinase (BTK) inhibitors, drugs utilized in cancer, are being repurposed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) (COVID-19). Recently, BTK inhibitors acalabrutinib and ibrutinib have been found to protect against pulmonary injury in a small group of patients infected with SARS-CoV-2. The high levels of pro-inflammatory cytokines found in the circulation of COVID-19 patients with severe lung disease suggest the involvement of the innate immune system in this process. Understanding the potential mechanism of action of BTK inhibition in SARS-CoV-2 is clearly of importance to determine how acalabrutinib, ibrutinib and possibly other BTK inhibitors may provide protection against lung injury.

scholarly journals Discovery of Tricyclic Pyranochromenone as Novel Bruton’s Tyrosine Kinase Inhibitors with In Vivo Antirheumatic Activity

2020 ◽  
Vol 21 (21) ◽  
pp. 7919
Author(s):  
Hyewon Cho ◽  
Eun Lee ◽  
Hye Ah Kwon ◽  
Lee Seul ◽  
Hui-Jeon Jeon ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Docking Study ◽  
Bruton’S Tyrosine Kinase ◽  
Collagen Induced Arthritis ◽  
Bruton's Tyrosine Kinase ◽  
Ic50 Values ◽  
Novel Scaffold ◽  
Btk Inhibitors

Bruton’s tyrosine kinase (BTK) is an attractive target for treating patients with B cell malignancies and autoimmune diseases. Many BTK inhibitors have been identified; however, like other kinase inhibitors, they lack diversity in their core structures. Therefore, it is important to secure a novel scaffold that occupies the adenine-binding site of BTK. We screened an in-house library of natural products and their analogs via a biochemical assay to identify a novel scaffold for targeting BTK. A pyranochromenone scaffold, derived from a natural active component decursin, was found to be effective at targeting BTK and was selected for further optimization. A series of pyranochromenone analogs was synthesized through the modification of pyranochromenone at the C7 position. Pyranochromenone compounds with an electrophilic warhead exhibited promising BTK inhibitory activity, with IC50 values in the range of 0.5–0.9 µM. A docking study of the representative compound 8 provided a reasonable explanation for compound activity. Compound 8 demonstrated good selectivity over other associated kinases and decreased the production of proinflammatory cytokines in THP cells. Moreover, compound 8 presented significant in vivo efficacy in a murine model of collagen-induced arthritis.

scholarly journals Bruton’s Tyrosine Kinase Inhibitors Ibrutinib and Acalabrutinib Counteract Anthracycline Resistance in Cancer Cells Expressing AKR1C3

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3731
Author(s):  
Anselm Morell ◽  
Lucie Čermáková ◽  
Eva Novotná ◽  
Lenka Laštovičková ◽  
Melodie Haddad ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Anthracycline Resistance ◽  
Target Action ◽  
Combination Regimens ◽  
Btk Inhibitors

Over the last few years, aldo-keto reductase family 1 member C3 (AKR1C3) has been associated with the emergence of multidrug resistance (MDR), thereby hindering chemotherapy against cancer. In particular, impaired efficacy of the gold standards of induction therapy in acute myeloid leukaemia (AML) has been correlated with AKR1C3 expression, as this enzyme metabolises several drugs including anthracyclines. Therefore, the development of selective AKR1C3 inhibitors may help to overcome chemoresistance in clinical practice. In this regard, we demonstrated that Bruton’s tyrosine kinase (BTK) inhibitors ibrutinib and acalabrutinib efficiently prevented daunorubicin (Dau) inactivation mediated by AKR1C3 in both its recombinant form as well as during its overexpression in cancer cells. This revealed a synergistic effect of BTK inhibitors on Dau cytotoxicity in cancer cells expressing AKR1C3 both exogenously and endogenously, thus reverting anthracycline resistance in vitro. These findings suggest that BTK inhibitors have a novel off-target action, which can be exploited against leukaemia through combination regimens with standard chemotherapeutics like anthracyclines.

scholarly journals Discovery of new BTK inhibitors with B cell suppression activity bearing a 4,6-substituted thieno[3,2-d]pyrimidine scaffold

RSC Advances ◽  
2017 ◽  
Vol 7 (42) ◽  
pp. 26060-26069 ◽  
Author(s):  
Qiumeng Zhang ◽  
Luyao Zhang ◽  
Jie Yu ◽  
Heng Li ◽  
Shijun He ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
B Cell ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Bruton’S Tyrosine Kinase ◽  
Immunosuppressive Activity ◽  
Bruton's Tyrosine Kinase ◽  
Low Toxicity ◽  
Cell Suppression ◽  
Btk Inhibitors

Seventeen compounds with 4,6-substituted thieno[3,2-d]pyrimidine scaffold were prepared as new Bruton's tyrosine kinase inhibitors. Compound 8 exhibits anti-BTK activity, immunosuppressive activity, enzymatic selectivity and low toxicity.

Development of Bruton’s Tyrosine Kinase Inhibitors for Rheumatoid Arthritis

2019 ◽  
Vol 25 (42) ◽  
pp. 5847-5859 ◽  
Author(s):  
Jiahui Lv ◽  
Jingde Wu ◽  
Feng He ◽  
Ying Qu ◽  
Qiuqiong Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Kinase Inhibitors ◽  
Hot Spot ◽  
Work Force ◽  
Activation Process ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Btk Inhibitors

Rheumatoid Arthritis (RA) is a chronic autoimmune disease and becomes one of the major causes of disability and work force loss. The presence of abnormal B cell and autoantibodies produced by most RA patients, primarily ACPA and RF, indicate that the function of B cell was involved in the development of RA disease. Accordingly, the drug targeting B cell has become a hot spot in the treatment of RA. Studies have shown that Bruton's tyrosine kinase (BTK) is involved in the regulation of B cell proliferation and activation process. Some small molecule BTK inhibitors have shown excellent inhibition in biological activity analysis and animal models. Therefore, this review will briefly introduce BTK and its role in cell signaling and overview recent progress of BTK inhibitors for RA treatment.

scholarly journals DESIGN AND SYNTHESIS OF SOME NEWER IMIDAZOLYL HETEROCYCLES AS POTENT BTK INHIBITORS FOR THE TREATMENT OF RHEUMATOID ARTHRITIS

2017 ◽  
Vol 9 (3) ◽  
pp. 80
Author(s):  
R. Priyadarsini ◽  
Anandhan Menaka
Keyword(s):  
Rheumatoid Arthritis ◽  
Hydrogen Bond ◽  
Molecular Docking ◽  
Tyrosine Kinase ◽  
Pharmacophore Model ◽  
Spectral Studies ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Hydrogen Bond Acceptor ◽  
Btk Inhibitors

Objective: The rheumatoid arthritis as a global health problem over the past few decades, Emphasizes the need for discovery of new therapeutic disease modifying anti-rheumatoid Arthritis drugs (DMARD’s). Bruton’s tyrosine kinase (BTK) is a cytoplasmic, non-receptor, tyrosine kinase which is expressed in most of the hematopoietic cells and plays an important role in the development, differentiation and proliferation of B-lineage cells, thus making BTK an efficient therapeutic target for the treatment of rheumatoid arthritis. This prompted us to synthesise a novel series of Imidazolyl Heterocycles as potent BTK (Bruton’s Tyrosine Kinase) inhibitors with alleged Anti-Rheumatoid Arthritis properties. Methods: Newer BTK inhibitors containing one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD) and three hydrophobic features based on that pharmacophore model for BTK were designed. The designed compounds were sorted by applying ADMET properties, Lipinski rule of five, molecular docking and Novelty prediction to refine the designed ligands. Finally, different five compounds containing Imidazole as the heterocyclic nucleus have been synthesized and characterized by different analytical methods like Chromatographic data, Elemental analysis and Spectral studies by IR, 1H NMR, 13C NMR, GC-MS. Molecular docking studies were performed against BTK using GLIDE 10.2. Results: Several important hydrogen bonds with BTK were revealed, which include the gatekeeper residue Glu475 and Met477 at the hinge region. Conclusion: Overall, this study suggests that the proposed ligands are found to be more effective BTK inhibitor as Anti-Rheumatoid arthritis agents.

Bruton’s tyrosine kinase (BTK) inhibitors in treating cancer: a patent review (2010-2018)

2019 ◽  
Vol 29 (4) ◽  
pp. 217-241 ◽  
Author(s):  
Yifan Feng ◽  
Weiming Duan ◽  
Xiaochuan Cu ◽  
Chengyuan Liang ◽  
Minhang Xin
Keyword(s):  
Tyrosine Kinase ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Patent Review ◽  
Btk Inhibitors
Sign in / Sign up

Export Citation Format

Share Document