6 Protein Tyrosine Kinase Inhibitors

Groundwater, Paul W.; Solomons, K. R. H.; Drewe, Jacqueline A.; Munawar, Munawar Ali

doi:10.1016/s0079-6468(08)70307-2

Cited by 33 publications

(30 citation statements)

References 216 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that basolateral 17.5 M genistein, a broad-spectrum tyrosine kinase inhibitor (1,24), virtually eliminates the CO 2 sensitivity of J HCO 3 . Basolateral 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo [3,4-d]pyrimidase (PP2), which inhibits the Src family (26) sTK, the Bcr-Abl sTK, as well as the Kit (53) RTK, is without effect at either 250 nM or 2 M. On the other hand, basolateral 35 nM PD168393, which blocks RTKs in the erbB (i.e., EGF receptor) family by alkylating a cysteine residue in the ATP binding pocket (19), blocks the CO 2 -induced increase in J HCO 3 .…”

mentioning

confidence: 76%

“…To test the hypothesis that the PT's CO 2 -sensing mechanism may require a RTK or an sTK, we examined the effects of basolateral genistein (1,24) In the first group of experiments, we examined effect of basolateral 7 M genistein with equilibrated 5% CO 2 /22 mM HCO 3 Ϫ in both the lumen (solution 2) and the bath (solution 4). During the first collection period, no drug was present (E in Fig.…”

Section: Effects Of Basolateral Genistein On Basolateral Co 2 Dependementioning

confidence: 99%

“…Genistein is a broad-spectrum tyrosine-kinase inhibitor (24) that blocks both sTKs (e.g., Src family) and RTKs (e.g., erbB family) but exhibits no nonspecific inhibition with other kinases (PKA, PKC) at the concentration we used (24). As showed in Fig.…”

Section: Inhibitor Specificitymentioning

confidence: 99%

See 2 more Smart Citations

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

Zhou¹,

Bouyer²,

Boron³

2006

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

. Role of a tyrosine kinase in the CO 2-induced stimulation of HCO 3 Ϫ reabsorption by rabbit S2 proximal tubules. Am J Physiol Renal Physiol 291: F358 -F367, 2006; doi:10.1152/ajprenal.00520.2005.-A previous study demonstrated that proximal tubule cells regulate HCO 3 Ϫ reabsorption by sensing acute changes in basolateral CO2 concentration, suggesting that there is some sort of CO2 sensor at or near the basolateral membrane (Zhou Y, Zhao J, Bouyer P, and Boron WF Proc Natl Acad Sci USA 102: 3875-3880, 2005). Here, we hypothesized that an early element in the CO 2 signal-transduction cascade might be either a receptor tyrosine kinase (RTK) or a receptorassociated (or soluble) tyrosine kinase (sTK). In our experiments, we found, first, that basolateral 17.5 M genistein, a broad-spectrum tyrosine kinase inhibitor, virtually eliminates the CO 2 sensitivity of HCO 3 Ϫ absorption rate (J HCO 3 ). Second, we found that neither basolateral 250 nM nor basolateral 2 M PP2, a high-affinity inhibitor for the Src family that also inhibits the Bcr-Abl sTK as well as the Kit RTK, reduces the CO 2-stimulated increase in J HCO 3 . Third, we found that either basolateral 35 nM PD168393, a high-affinity inhibitor of RTKs in the erbB (i.e., EGF receptor) family, or basolateral 10 nM BPIQ-I, which blocks erbB RTKs by competing with ATP, eliminates the CO2 sensitivity. In conclusion, the transduction of the CO2 signal requires activation of a tyrosine kinase, perhaps an erbB. The possibilities include the following: 1) a TK is simply permissive for the effect of CO 2 on J HCO 3 ; 2) a CO2 receptor activates an sTK, which would then raise J HCO 3 ; 3) a CO2 receptor transactivates an RTK; and 4) the CO2 receptor could itself be an RTK.kidney; out-of-equilibrium solutions; acid-base; volume reabsorption; signal transduction RENAL TUBULE CELLS PLAY A central role in whole body acid-base balance by 1) secreting H ϩ into the tubule lumen, thereby titrating NH 3 to NH 4 ϩ and also creating titratable acid; and 2) moving an equivalent amount of "new HCO 3 Ϫ " into the blood, ϳ70 mmol/day in humans, and thereby titrating the fixed acid produced by metabolism and generated by the gastrointestinal tract. At the same time, the tubules must also reabsorb nearly all of a much larger amount of HCO 3 Ϫ filtered in the glomeruli. The proximal tubule (PT) is the site of generation of ϳ60% of the new HCO 3 Ϫ and the site of reabsorption of ϳ80% of the filtered HCO 3 Ϫ , using the same transporters in both processes. The cell uses cytosolic carbonic anhydrase II (51, 52) to convert CO 2 ϩ H 2 O to H ϩ ϩ HCO 3 Ϫ , and then extrudes the H ϩ across the apical membrane (3, 10, 50) via Na/H exchangers (6, 7, 34) and H ϩ pumps (22) and exports the HCO 3 Ϫ across the basolateral membrane, mainly via the electrogenic Na-HCO 3 cotransporter (11,16,47,48). For the system to work properly, the PT cell must be able to respond to changes in whole body acid-base status by appropriately adjusting transporters activities.To study how the PT senses changes in whole bo...

show abstract

mentioning

confidence: 76%

Section: Effects Of Basolateral Genistein On Basolateral Co 2 Dependementioning

confidence: 99%

See 1 more Smart Citation

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

Zhou¹,

Bouyer²,

Boron³

2006

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Quercetin, a flavonoid that occurs in many fruits and vegetables (17), is a nonspecific inhibitor of protein kinases (18) and suppresses TNF-induced NF-B activation (19). The inhibitor blocks the degradation of IB␣ and the consequent translocation of the NF-B p65 subunit (19).…”

mentioning

confidence: 99%

IκB Kinases α and β Show a Random Sequential Kinetic Mechanism and Are Inhibited by Staurosporine and Quercetin

Peet

1999

Journal of Biological Chemistry

View full text Add to dashboard Cite

Activation of transcription factor NF-B is regulated by phosphorylation and subsequent degradation of its inhibitory subunit IB. The signal-induced phosphorylation of IB involves two IB kinases, IKK␣ and IKK␤. In the present study, we investigated the kinetic mechanisms of IKK␣ and IKK␤ by substrate and product inhibition. For both IKK␣ and IKK␤, the product ADP was a competitive inhibitor versus ATP and a non-competitive inhibitor versus IB␣. An alternative peptide substrate, IB␣-(21-41), was a competitive inhibitor versus IB␣ and a non-competitive inhibitor versus ATP for both kinases. These results rigorously eliminate the possibility of an ordered sequential mechanism and demonstrate that both kinases have a random sequential bi bi mechanism. Two natural compounds, quercetin and staurosporine, had previously been shown to inhibit the NF-B pathway, but the molecular target(s) of these compounds in the event had not been established. Here we demonstrate that quercetin and staurosporine potently inhibit both IKK␣ and IKK␤. Daidzein, a quercetin analogue that does not inhibit NF-B activation, showed no significant inhibition of either enzyme. This suggests that the inhibitory properties of quercetin and staurosporine in the NF-B pathway are mediated in part by their inhibition of IKK␣ and IKK␤. Mechanism studies reveal that staurosporine is a competitive inhibitor versus ATP, whereas quercetin serves as a mixed type inhibitor versus ATP. The strong inhibition of IKK␤ by staurosporine (K i ‫؍‬ 172 nM) and ADP (K i ‫؍‬ 136 nM) provides a rationale and structural framework for designing potent ATP-site inhibitors of IKK␤, which is an attractive drug target for inflammatory diseases.The transcription factor NF-B is regulated by the signaling of receptors for inflammatory cytokines such as TNF␣, 1 interleukin-1, or other external stimuli (1). In resting cells, NF-B is sequestered in the cytoplasm through its association with inhibitory proteins termed IB. When cells are stimulated by TNF␣ or interleukin-1, IB proteins (IB␣ and IB␤) are rapidly phosphorylated at Ser residues in the N-terminal region (2, 3). Phosphorylated IB␣ and IB␤ are subsequently ubiquitinated and undergo ubiquitin-dependent degradation by the 26 S proteasome (3, 4). Degradation of IB results in the release of NF-B which then translocates to the nucleus where it up-regulates the transcription of target genes (1).IB␣ and IB␤ are phosphorylated by a 500 -900-kDa IB kinase (IKK) (5, 6). Two kinases in the IKK complex, denoted IKK␣ and IKK␤ (or IKK-1 and IKK-2), phosphorylate IB␣ at the specific Ser residues that target the protein for ubiquitination and degradation (5-9). Both IKK␣ and IKK␤ contribute to the activity of the IKK complex and are involved in NF-B activation (5-9). The physiological function of these protein kinases was recently explored by analysis of IKK␣-deficient or IKK␤-deficient mice (10 -15). Mouse embryonic fibroblast cells that were isolated from IKK␤(Ϫ/Ϫ) embryos showed a marked reduction in TNF␣-and interleukin-1-induced NF-B ...

show abstract

“…[4][5][6][7][8][9][10] To date, the large majority of known protein kinase inhibitors are competitors of ATP. 6,11,12 The ATP binding site of protein kinases is relatively conserved; 13,14 therefore inhibitor selectivity has been an important concern. Among the many reported classes of protein kinase inhibitors, the 4-anilinoquinazolines have played a particularly important role in demonstrating the potential for selectivity and potency.…”

Section: Introductionmentioning

confidence: 99%

Termination of Color Charges

2000

J. Med. Chem.

View full text Add to dashboard Cite

4-Anilinoquinazolines represent an important class of protein kinase inhibitor. Modes of binding for two members of this inhibitor class were determined by X-ray crystallographic analysis of one inhibitor (4-[3-hydroxyanilino]-6,7-dimethoxyquinazoline) in complex with cyclin-dependent kinase 2 (CDK2) and the other (4-[3-methylsulfanylanilino]-6,7-dimethoxyquinazoline) in complex with p38 kinase. In both inhibitor/kinase structures, the 4-anilinoquinazoline was bound in the ATP site with the quinazoline ring system oriented along the peptide strand that links the two domains of the protein and with the anilino substituent projecting into a hydrophobic pocket within the protein interior. In each case, the nitrogen at position-1 of the quinazoline accepted a hydrogen bond from a backbone NH (CDK2, Leu-83; p38, Met-109) of the domain connector strand, and aromatic hydrogen atoms at C2 and C8 interacted with backbone carbonyl oxygen atoms of the peptide strand. The anilino group of the CDK2-bound compound was essentially coplanar with the quinazoline ring system and occupied a pocket between Lys-33 and Phe-80. For the p38-bound inhibitor, the anilino group was angled out of plane and was positioned between Lys-53 and Thr-106 in a manner similar to that observed for the aryl substituent of the pyridinylimidazole class of inhibitor.

show abstract

6 Protein Tyrosine Kinase Inhibitors

Cited by 33 publications

References 216 publications

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

IκB Kinases α and β Show a Random Sequential Kinetic Mechanism and Are Inhibited by Staurosporine and Quercetin

Termination of Color Charges

Contact Info

Product

Resources

About

6 Protein Tyrosine Kinase Inhibitors

Cited by 33 publications

References 216 publications

Role of a tyrosine kinase in the CO2-induced stimulation of HCO3−reabsorption by rabbit S2 proximal tubules

Role of a tyrosine kinase in the CO2-induced stimulation of HCO3−reabsorption by rabbit S2 proximal tubules

IκB Kinases α and β Show a Random Sequential Kinetic Mechanism and Are Inhibited by Staurosporine and Quercetin

Termination of Color Charges

Contact Info

Product

Resources

About

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules

Role of a tyrosine kinase in the CO₂-induced stimulation of HCO₃⁻reabsorption by rabbit S2 proximal tubules