The discovery of potent cRaf1 kinase inhibitors

Lackey, Karen; Cory, Michael; Davis, Roderick; Frye, Stephen V.; Harris, Philip A.; Hunter, Robert N.; Jung, David; McDonald, Octerloney B.; McNutt, Robert W.; Peel, Michael R.; Rutkowske, Randy D.; Veal, James M.; Wood, Edgar R.

doi:10.1016/s0960-894x(99)00668-x

Cited by 197 publications

(121 citation statements)

References 11 publications

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“…Additionally, GW5074 did not affect MKK6, a kinase that activates p38 MAP kinase, another stress-activated MAP kinase implicated in neuronal apoptosis (Table 1). That GW5074 has no direct effect on p38 MAP kinase itself has previously been reported by Lackey et al (2000).…”

Section: Gw5074 Inhibits Lk-induced Apoptosis In Cerebellar Granule Nmentioning

confidence: 60%

“…GW5074 is a potent and specific inhibitor of c-Raf in vitro Lackey et al (2000), reported that GW5074 is a potent inhibitor of c-Raf with no effect on the activities of cdk1, cdk2, c-src, p38 MAP kinase, VEGFR2, and c-fms. We examined the effect of GW5074 on purified c-Raf in vitro and confirmed that GW5074 inhibits c-Raf (Table 1).…”

Section: Gw5074 Inhibits Lk-induced Apoptosis In Cerebellar Granule Nmentioning

confidence: 99%

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The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

Chin

Liu

Morrison

et al. 2004

Journal of Neurochemistry

110

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Cerebellar granule neurons undergo apoptosis when switched from a medium containing high potassium (HK) to one that has low potassium (LK). LK-induced cell death is blocked by GW5074 {5-Iodo-3-[(3,5-dibromo-4-hydroxyphenyl) methylene]-2-indolinone}, a synthetic drug that inhibits c-Raf activity in vitro. GW5074 has no direct effect on the activities of several apoptosis-associated kinases when assayed in vitro. In contrast to its effect in vitro, treatment of neurons with GW5074 causes c-Raf activation (when measured in vitro in the absence of the drug) and stimulates the Raf-MEK-ERK pathway. Treatment of neurons with GW5074 also leads to an increase in the activity of B-Raf, which is not inhibited by GW5074 in vitro at concentrations at which the drug exerts its neuroprotective effect. PD98059 and U0126, two distinct inhibitors of MEK, block the activation of ERK by GW5074 but have no effect on its ability to prevent cell death. Overexpression of a dominant-negative form of Akt does not reduce the efficacy of GW5074, demonstrating an Akt-independent mechanism of action. Neuroprotection is inhibited by SN-50, a specific inhibitor of nuclear factor-kappa B (NF-jB) and by the Ras inhibitor S-trans, trans-farnesylthiosalicylic acid (FTS) implicating NF-jB and Ras in the neuroprotective signaling pathway activated by GW5074. In addition to preventing LK-induced apoptosis, treatment with GW5074 protects against the neurotoxic effects of MPP+ and methylmercury in cerebellar granule neurons, and glutathione depletion-induced oxidative stress in cortical neurons. Furthermore, GW5074 prevents neurodegeneration and improves behavioral outcome in an animal model of Huntington's disease. Given its neuroprotective effect on distinct types of cultured neurons, in response to different neurotoxic stimuli, and in an animal model of neurodegeneration, GW5074 could have therapeutic value against neurodegenerative pathologies in humans.

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Section: Gw5074 Inhibits Lk-induced Apoptosis In Cerebellar Granule Nmentioning

confidence: 60%

Section: Gw5074 Inhibits Lk-induced Apoptosis In Cerebellar Granule Nmentioning

confidence: 99%

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

Chin

Liu

Morrison

et al. 2004

Journal of Neurochemistry

110

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“…We chose the Raf-1 inhibitor GW5074 to further demonstrate the involvement of ERK in the ET receptor upregulation after SHS. The specificity and efficacy of GW5074 for inhibiting Raf-1 in-vivo has been established in previous studies [32,33]. Lakey et al and Chin et al reported that GW5074 is a potent Raf-1 inhibitor and examined the effect of GW5074 on purified Raf-1 and confirmed that GW5074 selectively inhibits Raf-1 in vivo .…”

Section: Discussionmentioning

confidence: 81%

“…The ERK1/2 pathway is a major effector of Raf. Transient activation of Raf-1 contributes to alterations in smooth muscle cell function, such as enhanced contraction and proliferation, whereas sustained activation results in differentiation via the regulation of various ERK substances [33]. We chose the Raf-1 inhibitor GW5074 to further demonstrate the involvement of ERK in the ET receptor upregulation after SHS.…”

Section: Discussionmentioning

confidence: 99%

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

Cao

Zhang

et al. 2011

BMC Neurosci

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BackgroundCigarette smoking enhances the risk of stroke. However, the underlying molecular mechanisms are largely unknown. The present study established an in vivo rat secondhand cigarette smoking (SHS) model and examined the hypothesis that SHS upregulates endothelin receptors with increased cerebrovascular contraction via the Raf/extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK) pathway.ResultsRats were exposed to SHS for up to 8 weeks. The cerebral artery vasoconstriction was recorded by a sensitive myograph. The mRNA and protein expressions for endothelin receptors in cerebral arteries were studied by real-time PCR and Western blot. Compared to fresh air exposed rats, cerebral arteries from SHS rats exhibited stronger contractile responses (P < 0.05) mediated by endothelin type A (ETA) receptors. The expressions of mRNA and protein for ETA receptors in the cerebral arteries from SHS rats were higher (P < 0.05) than that in control. SHS did not affect endothelin type B (ETB) receptor-mediated contractions, mRNA or protein levels. The results suggest that SHS upregulates ETA, but not ETB receptors in vivo. After SHS exposure, the mRNA levels of Raf-1 and ERK1/2, the protein expression of phosphorylated (p)-Raf-1 and p-ERK1/2 were increased (P < 0.05). Raf-1 inhibitor, GW5074 suppressed the enhanced ETA receptor-mediated contraction, mRNA and protein levels induced by SHS. In addition, GW5074 inhibited the SHS-caused increased mRNA and phosphorylated protein levels of Raf-1 and ERK1/2, suggesting that SHS induces activation of the Raf/ERK/MAPK pathway.ConclusionsSHS upregulates cerebrovascular ETA receptors via the Raf/ERK/MAPK pathway, which provides novel understanding of mechanisms involved in SHS-associated stroke.

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“…The effects of GW5074 on CVB3 replication could not be countered by PI4KIIIβ-Y583M, which indicates that binding of this compound to PI4KIIIβ does not involve Y583 in the ATP-binding pocket. The inhibition of kinases by GW5074 can occur in a competitive manner with GW5074 acting as an ATP/GTP analog [41,42], or alternatively in a non-competitive manner, as exemplified by the prevention of hexamer formation of glutamate dehydrogenase [43,44]. The mechanism by which GW5074 inhibits PI4KIIIβ remains to be elucidated in future studies.…”

Section: Discussionmentioning

confidence: 99%

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

et al. 2012

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RNA viruses can rapidly mutate and acquire resistance to drugs that directly target viral enzymes, which poses serious problems in a clinical context. Therefore, there is a growing interest in the development of antiviral drugs that target host factors critical for viral replication, since they are unlikely to mutate in response to therapy. We recently demonstrated that phosphatidylinositol-4-kinase IIIβ (PI4KIIIβ) and its product phosphatidylinositol-4-phosphate (PI4P) are essential for replication of enteroviruses, a group of medically important RNA viruses including poliovirus (PV), coxsackievirus, rhinovirus, and enterovirus 71. Here, we show that enviroxime and GW5074 decreased PI4P levels at the Golgi complex by directly inhibiting PI4KIIIβ. Coxsackievirus mutants resistant to these inhibitors harbor single point mutations in the non-structural protein 3A. These 3A mutations did not confer compound-resistance by restoring the activity of PI4KIIIβ in the presence of the compounds. Instead, replication of the mutant viruses no longer depended on PI4KIIIβ, since their replication was insensitive to siRNA-mediated depletion of PI4KIIIβ. The mutant viruses also did not rely on other isoforms of PI4K. Consistently, no high level of PI4P could be detected at the replication sites induced by the mutant viruses in the presence of the compounds. Collectively, these findings indicate that through specific single point mutations in 3A, CVB3 can bypass an essential host factor and lipid for its propagation, which is a new example of RNA viruses acquiring resistance against antiviral compounds, even when they directly target host factors.

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The discovery of potent cRaf1 kinase inhibitors

Cited by 197 publications

References 11 publications

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

The c‐Raf inhibitor GW5074 provides neuroprotection in vitro and in an animal model of neurodegeneration through a MEK‐ERK and Akt‐independent mechanism

Secondhand smoke exposure induces Raf/ERK/MAPK-mediated upregulation of cerebrovascular endothelin ETA receptors

Coxsackievirus mutants that can bypass host factor PI4KIIIβ and the need for high levels of PI4P lipids for replication

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