Tyrosine Kinase Inhibitors. 14. Structure−Activity Relationships for Methyl- amino-Substituted Derivatives of 4-[(3-Bromophenyl)amino]-6-(methylamino)- pyrido[3,4-d]pyrimidine (PD 158780), a Potent and Specific Inhibitor of the Tyrosine Kinase Activity of Receptors for the EGF Family of Growth Factors

1998 ◽  
Vol 41 (5) ◽  
pp. 742-751 ◽  
Author(s):  
Gordon W. Rewcastle ◽  
Donna K. Murray ◽  
William L. Elliott ◽  
David W. Fry ◽  
Curtis T. Howard ◽  
...  
Keyword(s):  
Growth Factors ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Specific Inhibitor ◽  
Tyrosine Kinase Activity ◽  
Structure Activity ◽  
Egf Family ◽  
Derivatives Of

Tyrosine kinase regulates epithelial sodium transport in A6 cells

1993 ◽  
Vol 264 (1) ◽  
pp. C246-C250 ◽  
Author(s):  
P. S. Matsumoto ◽  
A. Ohara ◽  
P. Duchatelle ◽  
D. C. Eaton
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Na Transport ◽  
Tyrosine Kinase Activity ◽  
Open Probability ◽  
Cyclic Monophosphate ◽  
Tyrphostin 23

Insulin increases epithelial Na+ reabsorption, and many of its actions involve tyrosine kinase. We used tyrosine kinase inhibitors to examine the role of tyrosine kinase in the action of insulin. Pretreatment of Na+ transporting cells with tyrosine kinase inhibitors attenuates the subsequent action of insulin, suggesting that the action of insulin on epithelial Na+ transport involves tyrosine kinase activity. In addition to their effect on insulin-induced Na+ transport, the tyrosine kinase inhibitors also significantly reduce Na+ transport in Na(+)-transporting epithelial cells, suggesting that there is a significant tonic tyrosine kinase activity that modulates epithelial Na+ transport. Using patch-clamp methods, we found that one inhibitor, genistein, reduces the number of active Na+ channels in cell-attached patches without significantly affecting the open probability of any remaining channels. The effects of the tyrosine kinase inhibitors are not due to inhibition of protein kinase A (PKA), since H89, a PKA inhibitor, does not affect Na+ transport of control cells (as the tyrosine kinase inhibitors do), and the tyrosine kinase inhibitor, genistein or tyrphostin 23, does not alter the stimulation of ion transport by 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate, a membrane-permeable adenosine 3',5'-cyclic monophosphate analogue (as H89 does).

Identification of surrogate markers for determining drug activity using proteomics

2003 ◽  
Vol 31 (6) ◽  
pp. 1488-1490 ◽  
Author(s):  
C.M. McClelland ◽  
W.J. Gullick
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Drug Evaluation ◽  
New Drugs ◽  
Hydroxyl Groups ◽  
Surrogate Markers ◽  
Tyrosine Kinase Activity ◽  
Drug Activity

In a high proportion of human carcinomas overexpression of the EGFR (epidermal growth factor receptor), a receptor tyrosine kinase, represents a potential target for cancer treatment. EGFR is induced to dimerize through ligand binding which activates the tyrosine kinase activity of the receptor. This catalyses the transfer of ATP's γ-phosphate to hydroxyl groups of tyrosine residues on the receptor, creating binding sites that recruit downstream signalling proteins. New drugs, SMTKIs (small-molecule tyrosine kinase inhibitors), have been designed to inhibit the tyrosine kinase activity of the receptor, producing an anti-tumour effect. The development of surrogate markers to determine the drug activity of these new inhibitors would be of great benefit in drug evaluation and in the subsequent management of patient disease. This review describes current treatments of cancer using tyrosine kinase inhibitors and the use of proteomic analysis to identify possible markers of activity of these new drugs.

Modulation of Excitability in Aplysia Tail Sensory Neurons by Tyrosine Kinases

2001 ◽  
Vol 85 (6) ◽  
pp. 2398-2411 ◽  
Author(s):  
Angela L. Purcell ◽  
Thomas J. Carew
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Sensory Neurons ◽  
Tyrosine Kinases ◽  
Kinase Activity ◽  
Kinase Inhibitors ◽  
Direct Injection ◽  
Tyrosine Phosphatase ◽  
Tyrosine Kinase Activity ◽  
Activity Dependent

Tyrosine kinases have recently been shown to modulate synaptic plasticity and ion channel function. We show here that tyrosine kinases can also modulate both the baseline excitability state of Aplysia tail sensory neurons (SNs) as well as the excitability induced by the neuromodulator serotonin (5HT). First, we examined the effects of increasing and decreasing tyrosine kinase activity in the SNs. We found that tyrosine kinase inhibitors decrease baseline SN excitability in addition to attenuating the increase in excitability induced by 5HT. Conversely, functionally increasing cellular tyrosine kinase activity in the SNs by either inhibiting opposing tyrosine phosphatase activity or by direct injection of an active tyrosine kinase (Src) induces increases in SN excitability in the absence of 5HT. Second, we examined the interaction between protein kinase A (PKA), which is known to mediate 5HT-induced excitability changes in the SNs, and tyrosine kinases, in the enhancement of SN excitability. We found that the tyrosine kinases function downstream of PKA activation since tyrosine kinase inhibitors reduce excitability induced by activators of PKA. Finally, we examined the role of tyrosine kinases in other forms of 5HT-induced plasticity in the SNs. We found that while tyrosine kinase inhibitors attenuate excitability produced by 5HT, they have no effect on short-term facilitation (STF) of the SN-motor neuron (MN) synapse induced by 5HT. Thus tyrosine kinases modulate different forms of SN plasticity independently. Such differential modulation would have important consequences for activity-dependent plasticity in a variety of neural circuits.

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