scholarly journals Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors

2021 ◽  
Vol 12 ◽  
Author(s):  
Rula Zain ◽  
Mauno Vihinen
Keyword(s):  
Tyrosine Kinase ◽  
Structure Function ◽  
Protein Tyrosine Kinase ◽  
Inflammatory Diseases ◽  
Binding Modes ◽  
Cellular Targets ◽  
Promising Target ◽  
Covalent Inhibitors ◽  
Autoimmune And Inflammatory Diseases ◽  
Btk Inhibitors

Low-molecular weight chemical compounds have a longstanding history as drugs. Target specificity and binding efficiency represent major obstacles for small molecules to become clinically relevant. Protein kinases are attractive cellular targets; however, they are challenging because they present one of the largest protein families and share structural similarities. Bruton tyrosine kinase (BTK), a cytoplasmic protein tyrosine kinase, has received much attention as a promising target for the treatment of B-cell malignancies and more recently autoimmune and inflammatory diseases. Here we describe the structural properties and binding modes of small-molecule BTK inhibitors, including irreversible and reversible inhibitors. Covalently binding compounds, such as ibrutinib, acalabrutinib and zanubrutinib, are discussed along with non-covalent inhibitors fenebrutinib and RN486. The focus of this review is on structure-function relationships.

scholarly journals Targeting Bruton tyrosine kinase using non-covalent inhibitors in B cell malignancies

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Danling Gu ◽  
Hanning Tang ◽  
Jiazhu Wu ◽  
Jianyong Li ◽  
Yi Miao
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
B Cell ◽  
Clinical Studies ◽  
Acquired Resistance ◽  
B Cell Malignancies ◽  
Bcr Signaling ◽  
Bruton Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Btk Inhibitors

AbstractB cell receptor (BCR) signaling is involved in the pathogenesis of B cell malignancies. Activation of BCR signaling promotes the survival and proliferation of malignant B cells. Bruton tyrosine kinase (BTK) is a key component of BCR signaling, establishing BTK as an important therapeutic target. Several covalent BTK inhibitors have shown remarkable efficacy in the treatment of B cell malignancies, especially chronic lymphocytic leukemia. However, acquired resistance to covalent BTK inhibitors is not rare in B cell malignancies. A major mechanism for the acquired resistance is the emergence of BTK cysteine 481 (C481)  mutations, which disrupt the binding of covalent BTK inhibitors. Additionally, adverse events due to the off-target inhibition of kinases other than BTK by covalent inhibitors are common. Alternative therapeutic options are needed if acquired resistance or intolerable adverse events occur. Non-covalent BTK inhibitors do not bind to C481, therefore providing a potentially effective option to patients with B cell malignancies, including those who have developed resistance to covalent BTK inhibitors. Preliminary clinical studies have suggested that non-covalent BTK inhibitors are effective and well-tolerated. In this review, we discussed the rationale for the use of non-covalent BTK inhibitors and the preclinical and clinical studies of non-covalent BTK inhibitors in B cell malignancies.

scholarly journals Induction of phagocytosis by a protein tyrosine kinase

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1175-1180 ◽  
Author(s):  
ZK Indik ◽  
JG Park ◽  
XQ Pan ◽  
AD Schreiber
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Protein Tyrosine Kinase ◽  
Specific Protein ◽  
Gamma Chain ◽  
Gamma Subunit ◽  
Protein Tyrosine ◽  
Cellular Targets ◽  
Surface Receptors ◽  
Extracellular Signals

The transmission of extracellular signals to cellular targets by many noncatalytic surface receptors is dependent on interaction between cytoplasmic protein tyrosine kinases (PTKs) and tyrosine-containing sequences in the cytoplasmic domain of the receptor or an associated subunit. Isoforms of each of the three classes of the noncatalytic Fc gamma receptors, Fc gamma RI, Fc gamma RII, and Fc gamma RIII, are able to transmit a phagocytic signal in transfected COS-1 cells. Both Fc gamma RI and Fc gamma RIIIA require the gamma subunit for this signaling event. The protein tyrosine kinase Syk dramatically enhances phagocytosis mediated by both these receptors and increases the number of cells able to mediate phagocytosis. Two gamma chain cytoplasmic YXXL sequences are required for this effect. The action of Syk is less pronounced on the phagocytic Fc gamma RII receptor, Fc gamma RIIA, which does not require the gamma chain for phagocytosis. However, Syk allows phagocytosis by the nonphagocytic Fc gamma RII receptor Fc gamma RIIB2, which contains only a single YXXL sequence, when an additional tyrosine-containing sequence, YMTL, is introduced. These studies indicate that the efficiency of phagocytosis is markedly enhanced by the presence of a specific protein tyrosine kinase.

Protein-tyrosine Kinase p72 syk Is Activated by Platelet Activating Factor in Platelets

1994 ◽  
Vol 72 (06) ◽  
pp. 937-941 ◽  
Author(s):  
Karim Rezaul ◽  
Shigeru Yanagi ◽  
Kiyonao Sada ◽  
Takanobu Taniguchi ◽  
Hirohei Yamamura
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Phosphorylation ◽  
Protein Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Critical Role ◽  
Platelet Activating Factor ◽  
Kinase Assay ◽  
Potential Candidate ◽  
Protein Tyrosine ◽  
Induced Aggregation

SummaryIt has been demonstrated that activation of platelets by platelet-activating factor (PAF) results in a dramatic increase in tyrosine phosphorylation of several cellular proteins. We report here that p72 syk is a potential candidate for the protein-tyrosine phosphorylation following PAF stimulation in porcine platelets. Immunoprecipitation kinase assay revealed that PAF stimulation resulted in a rapid activation of p72 syk which peaked at 10 s. The level of activation was found to be dose dependent and could be completely inhibited by the PAF receptor antagonist, CV3988. Phosphorylation at the tyrosine residues of p72 syk coincided with activation of yllsyk. Pretreatment of platelets with aspirin and apyrase did not affect PAF induced activation of p72 syk .Furthermore, genistein, a potent protein-tyrosine-kinase inhibitor, diminished PAF-induced p72 syk activation and Ca2+ mobilization as well as platelet aggregation. These results suggest that p72 syk may play a critical role in PAF-induced aggregation, possibly through regulation of Ca2+ mobilization.

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.

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