Inhibition of p56lckTyrosine Kinase by Isothiazolones

Trevillyan, James M.; Chiou, X. Grace; Ballaron, Stephen J.; Tang, Qiang; Buko, Alexander M.; Sheets, Michael P.; Smith, Morey L.; Putman, C. Brent; Wiedeman, Paul E.; Tu, Noah P.; Madar, David J.; Smith, Harriet T.; Gubbins, Earl J.; Warrior, Usha; Chen, Y.-W.; Mollison, Karl W.; Faltynek, Connie R.; Djurić, Stevan W.

doi:10.1006/abbi.1999.1099

Cited by 37 publications

(22 citation statements)

References 17 publications

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“…The addition of a thiol-reducing agent quenched this effect. Interaction of protein thiol groups has also been described for similar isothiazolones to those investigated here, which inhibit the interleukin-5 receptor (45), p56 lck (34), and telomerase (46). Interestingly, however, the original isothiazolone hits did not markedly inhibit telomerase using the telomeric repeat amplification protocol assay.…”

Section: Discussionsupporting

confidence: 60%

“…A chemical reaction scheme (Fig. 7) for the potential mechanism of isothiazolone reactivity has been proposed (34). It is likely that the covalent disulfide bridge of the drug-protein complex would be cleaved in the presence of excess thiol (e.g., cysteine and glutathione) to release the open-chain dihydro product as shown in Fig.…”

Section: Discussionmentioning

confidence: 99%

“…During the evaluation of the hits, it was realized that the HAT activity for this class of compounds may be due to a covalent binding to the enzyme via disulfide bond formation. It has been reported that the S-N bond of isothiazolones is reactive toward thiol groups as proposed for the mechanism of inhibition of p56 lck kinase (34). With this in mind, 35 analogues (27 N-aryl and 8 N-alkyl isothiazolones) were designed, prepared, and evaluated for HAT inhibition.…”

Section: Identification Of Isothiazolones As Inhibitors Of Hat Activimentioning

confidence: 99%

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Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Stimson

Rowlands

Newbatt

et al. 2005

Molecular Cancer Therapeutics

209

128

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Histone acetylation plays an important role in regulating the chromatin structure and is tightly regulated by two classes of enzyme, histone acetyltransferases (HAT) and histone deacetylases (HDAC). Deregulated HAT and HDAC activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anticancer agents. Several HDAC inhibitors have been described; however, few inhibitors of HATs have been disclosed. Following a FlashPlate highthroughput screen, we identified a series of isothiazolonebased HAT inhibitors. Thirty-five N-substituted analogues inhibited both p300/cyclic AMP -responsive element binding protein -binding protein -associated factor (PCAF) and p300 (1 to >50 Mmol/L, respectively) and the growth of a panel of human tumor cell lines (50% growth inhibition, 0.8 to >50 Mmol/L). CCT077791 and CCT077792 decreased cellular acetylation in a time-dependent manner (2 -48 hours of exposure) and a concentration-dependent manner (one to five times, 72 hours, 50% growth inhibition) in HCT116 and HT29 human colon tumor cell lines. CCT077791 reduced total acetylation of histones H3 and H4, levels of specific acetylated lysine marks, and acetylation of A-tubulin. Four and 24 hours of exposure to the compounds produced the same extent of growth inhibition as 72 hours of continuous exposure, suggesting that growth arrest was an early event. Chemical reactivity of these compounds, as measured by covalent protein binding and loss of HAT inhibition in the presence of DTT, indicated that reaction with thiol groups might be important in their mechanism of action. As one of the first series of small-molecule inhibitors of HAT activity, further analogue synthesis is being pursued to examine the potential scope for reducing chemical reactivity while maintaining HAT inhibition. [Mol Cancer Ther 2005;4(10):1521 -32]

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 99%

Section: Identification Of Isothiazolones As Inhibitors Of Hat Activimentioning

confidence: 99%

See 1 more Smart Citation

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Stimson

Rowlands

Newbatt

et al. 2005

Molecular Cancer Therapeutics

209

128

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“…Although HIV-tat has been used to design therapeutics for AIDS patients (49), our results suggest that inhibitors of p56 lck enzyme may also have significant therapeutic potential. Isothiazolones have been shown to inhibit p56 lck (50), and thus may prove useful in blocking HIV-1 replication.…”

Section: Discussionmentioning

confidence: 99%

Differential Requirement for p56lck in HIV-tat Versus TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Kinase, and Apoptosis

Manna

Aggarwal

2000

The Journal of Immunology

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HIV-tat protein, like TNF, activates a wide variety of cellular responses, including NF-κB, AP-1, c-Jun N-terminal kinase (JNK), and apoptosis. Whether HIV-tat transduces these signals through the same mechanism as TNF is not known. In the present study we investigated the role of the T cell-specific tyrosine kinase p56lck in HIV-tat and TNF-mediated cellular responses by comparing the responses of Jurkat T cells with JCaM1 cells, an isogeneic lck-deficient T cell line. Treatment with HIV-tat protein activated NF-κB, degraded IκBα, and induced NF-κB-dependent reporter gene expression in a time-dependent manner in Jurkat cells but not in JCaM1 cells, suggesting the critical role of p56lck kinase. These effects were specific to HIV-tat, as activation of NF-κB by PMA, LPS, H2O2, and TNF was minimally affected. p56lck was also found to be required for HIV-tat-induced but not TNF-induced AP-1 activation. Similarly, HIV-tat activated the protein kinases JNK and mitogen-activated protein kinase kinase in Jurkat cells but not in JCaM1 cells. HIV-tat also induced cytotoxicity, activated caspases, and reactive oxygen intermediates in Jurkat cells, but not in JCaM1 cells. HIV-tat activated p56lck activity in Jurkat cells. Moreover, the reconstitution of JCaM1 cells with p56lck tyrosine kinase reversed the HIV-tat-induced NF-κB activation and cytotoxicity. Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-κB, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF.

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“…Thiol oxidation is involved in many cellular processes, e.g., p38 mitogen-activating protein (MAP) kinase activation (2,23), inhibition of p56 (lck) tyrosine kinase (22), activation of protein phosphatases (3,15,17), pulmonary artery vasoconstriction (11), and pulmonary vasodilation (19). Although H 2 O 2 appears to exert many biological effects via thiol oxidation, it is enigmatic that the kinetics for this reaction are relatively slow (18 -26 mol Ϫ1 s Ϫ1 ) (24).…”

mentioning

confidence: 99%

Redox-dependent coronary metabolic dilation

Saitoh¹,

Kiyooka²,

Ročić³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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We have observed that hydrogen peroxide (H 2O2), the dismutated product of superoxide, is a coronary metabolic dilator and couples myocardial oxygen consumption to coronary blood flow. Because the chemical activity of H 2O2 favors its role as an oxidant, and thiol groups are susceptible to oxidation, we hypothesized that coronary metabolic dilation occurs via a redox mechanism involving thiol oxidation. To test this hypothesis, we studied the mechanisms of dilation of isolated coronary arterioles to metabolites released by metabolically active (paced at 400 min) isolated cardiac myocytes and directly compared these responses with authentic H2O2. Studies were performed under control conditions and using interventions designed to reduce oxidized thiols [0.1 M dithiothreitol (DTT) and 10 mM N-acetyl-L-cysteine (NAC)]. Aliquots of the conditioned buffer from paced myocytes produced vasodilation of isolated arterioles (peak response, 71% Ϯ 6% of maximal dilation), whereas H 2O2 produced complete dilation (92% Ϯ 7%). Dilation to either the conditioned buffer or to H 2O2 was significantly reduced by the administration of either NAC or DTT. The location of the thiols oxidized by the conditioned buffer or of H 2O2 was determined by the administration of the fluorochromes monochlorobimane (20 M) or monobromotrimethylammoniobimane (20 M), which covalently label the reduced total or extracellular-reduced thiols, respectively. H 2O2 or the conditioned buffer predominately oxidized intracellular thiols since the fluorescent signal from monochlorobimane was reduced more than that of monobromotrimethylammoniobimane. To determine whether one of the intracellular targets of thiol oxidation that leads to dilation is the redoxsensitive kinase p38 mitogen-activated protein (MAP) kinase, we evaluated dilation following the administration of the p38 inhibitor SB-203580 (10 M). The inhibition of p38 attenuated dilation to either H2O2 or to the conditioned buffer from stimulated myocytes by a similar degree, but SB-203580 did not attenuate dilation to nitroprusside. Western blot analysis for the activated form of p38 (phospho-p38) in the isolated aortae revealed robust activation of this enzyme by H2O2. Taken together, our results show that an active component of cardiac metabolic dilation, like that of H2O2, produces dilation by the oxidation of thiols, which are predominately intracellular and dependent activation on the p38 MAP kinase. Thus coronary metabolic dilation appears to be mediated by redox-dependent signals. coronary circulation; coronary microcirculation; reactive oxygen species; vasodilatation THE OXIDATION OF THIOL GROUPS is involved in many biological processes. Thiol oxidation induces protein conformation changes by converting the free thiols (-SH) into sulfenic acids (SO Ϫ ), sulfinic acids (SOO Ϫ ), sulfonic acids (SOOO Ϫ ), and disulfide bridges (S-S). Thiol oxidation is involved in many cellular processes, e.g., p38 mitogen-activating protein (MAP) kinase activation (2, 23), inhibition of p56 (lck) tyrosine kinase ...

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Inhibition of p56lckTyrosine Kinase by Isothiazolones

Cited by 37 publications

References 17 publications

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Isothiazolones as inhibitors of PCAF and p300 histone acetyltransferase activity

Differential Requirement for p56lck in HIV-tat Versus TNF-Induced Cellular Responses: Effects on NF-κB, Activator Protein-1, c-Jun N-Terminal Kinase, and Apoptosis

Redox-dependent coronary metabolic dilation

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