Flipped Out:  Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors

Aronov, Alex M.; Baker, Christopher T. H.; Bemis, Guy W.; Cao, Jingrong; Chen, Guanjing; Ford, Pamella J.; Germann, Ursula A.; Green, Jeremy; Hale, Michael R.; Jacobs, Marc; Janetka, James W.; Maltais, François; Martínez-Botella, Gabriel; Namchuk, Mark; Straub, Judy; Tang, Qing; Xie, Xin

doi:10.1021/jm061381f

Cited by 112 publications

(102 citation statements)

References 15 publications

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“…Binding of BVD-523 to ERK2 was demonstrated using calorimetric studies and compared with data generated using the ERK inhibitors SCH772984 (26) and pyrazolylpyrrole (31). All compounds bound and stabilized inactive ERK2 with increasing concentration, as indicated by positive DTm values (Fig.…”

Section: Resultsmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

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184

145

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Aberrant activation of signaling through the RAS-RAF-MEK-ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro BVD-523 treatment resulted in reduced proliferation and enhanced caspase activity in sensitive cells. Interestingly, BVD-523 inhibited phosphorylation of target substrates despite increased phosphorylation of ERK1/2. In in vivo xenograft studies, BVD-523 showed dose-dependent growth inhibition and tumor regression. BVD-523 yielded synergistic antiproliferative effects in a BRAF V600E -mutant melanoma cell line xenograft model when used in combination with BRAF inhibition. Antitumor activity was also demonstrated in in vitro and in vivo models of acquired resistance to singleagent and combination BRAF/MEK-targeted therapy. On the basis of these promising results, these studies demonstrate BVD-523 holds promise as a treatment for ERK-dependent cancers, including those whose tumors have acquired resistance to other treatments targeting upstream nodes of the MAPK pathway. Assessment of BVD-523 in clinical trials is underway

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Section: Resultsmentioning

confidence: 99%

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Germann

Furey

Markland

et al. 2017

Molecular Cancer Therapeutics

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184

145

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“…VOLUME 290 • NUMBER 2 • JANUARY 9, 2015 tivity against ERK when tested against a panel of 184 related kinases (48,49), and FR180 displays a high selectivity against ERK when tested against eight related kinases (50). As shown in Fig.…”

Section: Journal Of Biological Chemistrymentioning

confidence: 99%

A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells

López-Cotarelo

Escribano-Díaz

González-Bethencourt

et al. 2015

Journal of Biological Chemistry

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Background: Chemokine receptor CCR7 promotes survival in mature dendritic cells (mDCs). Results: Activated AMP-dependent kinase (AMPK) induces apoptosis in mDCs; CCR7 uses the kinases MEK1/2-ERK1/2 to regulate phosphorylation of AMPK on Ser-485 and consequently its inhibition. Conclusion: CCR7 uses a novel MEK1/2-ERK1/2-AMPK signaling axis to induce survival in mDCs. Significance: AMPK is a potential target to regulate mDC-mediated immune responses.

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“…Furegrelate (TxAS-specific inhibitor), SQ29548 (TxA 2 receptor antagonist, also known as TxA 2 functional antagonist; Nie et al, 2004), U46619 (TxA 2 receptor agonist, also known as TxA 2 mimetic; Li et al, 2007), CAY10561 (ERK-specific inhibitor; Aronov et al, 2007) and SP600125 (the JNK inhibitor) were purchased from Cayman Chemical. NNK and SB203580 (p38 MAPK-specific inhibitor) were obtained from Toronto Research Chemicals Inc. (Toronto, North York, Canada).…”

Section: Chemicals and Drug Treatmentmentioning

confidence: 99%

“…The PI3K-specific inhibitor, wortmannin, was purchased from Sigma Chemical Co. (St Louis, MO, USA). The concentrations of all chemicals used were based on the product datasheets and previous publications (Daniel et al, 1999;de Leval et al, 2006;Aronov et al, 2007;Li et al, 2007;Wei et al, 2007;Cailleteau et al, 2008;Moussa et al, 2008a, b), and they were proven to be optimal in the present study. Dimethylsulfoxide, an organic solvent, was used in the treatment with different drugs.…”

Section: Chemicals and Drug Treatmentmentioning

confidence: 99%

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

Huang

Hsin

et al. 2010

Oncogene

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The role of thromboxane A 2 (TxA 2 ) in smokingassociated lung cancer is poorly understood. This study was conducted to study the role of TxA 2 in smoking carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-promoted cell survival and growth in human lung cancer cells. We found that NNK increased TxA 2 synthase (TxAS) expression and thromboxane B 2 (TxB 2 ) generation in cultured lung cancer cells, the result of which was supported by the increased level of TxAS in lung cancer tissues of smokers. Both TxAS-specific inhibitor furegrelate and TxA 2 receptor antagonist SQ29548 completely blocked NNK-mediated cell survival and growth via inducting apoptosis. TxA 2 receptor agonist U46619 reconstituted a near-full survival and growth response to NNK when TxAS was inhibited, affirming the role of TxA 2 receptor in NNK-mediated cell survival and growth. Suppression of cyclic adenosine monophosphate response element binding protein (CREB) activity by its small interference RNA blocked the effect of NNK. Phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated kinase (ERK) also had a positive role. Altogether, our results have revealed that NNK stimulates TxA 2 synthesis and activates its receptor in lung cancer cells. The increased TxA 2 may then activate CREB through PI3K/Akt and extracellular ERK pathways, thereby contributing to the NNK-promoted survival and growth of lung cancer cells.

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Flipped Out: Structure-Guided Design of Selective Pyrazolylpyrrole ERK Inhibitors

Cited by 112 publications

References 15 publications

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

A Novel MEK-ERK-AMPK Signaling Axis Controls Chemokine Receptor CCR7-dependent Survival in Human Mature Dendritic Cells

4-Methylnitrosamino-1-3-pyridyl-1-butanone (NNK) promotes lung cancer cell survival by stimulating thromboxane A2 and its receptor

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