Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway

Flaherty, Patrick; Chopra, Ishveen; Jain, Prashi; Yi, Shuyan; Allen, Erika; Cavanaugh, Jane E.

doi:10.1016/j.bmcl.2010.03.033

Cited by 15 publications

(11 citation statements)

References 36 publications

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“…MAPKs are activated by signaling molecules such as growth factors, cytokines, neurotransmitters, hormones or various cell stressors which generally transmit their signaling through tyrosine kinase, G-coupled protein or hormone receptors(28). In MAPKs pathways, signals are transduced through a three-tiered kinase signaling cascade which begins with the phosphorylation of a mitogen-activated kinase kinase kinase (MAPKKK) that phosphorylates a second mitogen-activated kinase kinase (MAPKK) which subsequently phosphorylates a third mitogen-activated kinase (MAPK).…”

Section: Overview Of Mapksmentioning

confidence: 99%

“…Long dose response analysis, the process of evaluating the drug’s efficacy at five concentration levels, is completed for compounds that exhibit significant growth inhibition during single dose analysis. Investigators are continuing studies on variations of this compound for their potential to inhibit EGF-mediated activation of the MEK5/ERK5 signaling pathway (111). …”

Section: Inhibitors Of Mek5/erk5mentioning

confidence: 99%

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MEK5/ERK5 pathway: The first fifteen years

Drew

Burow

Beckman

2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

140

198

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While conventional MAP kinase pathways are one of the most highly studied signal transduction molecules, less is known about the MEK5 signaling pathway. This pathway has been shown to play a role in normal cell growth cycles, survival and differentiation. This MEK5 pathway is also believed to mediate the effects of a number of oncogenes. MEK5 is the upstream activator of ERK5 in many epithelial cells. Activation of the MEK-MAPK pathway is a frequent event in malignant tumor formation and contributes to chemoresistance and anti-apoptotic signaling. This pathway may be involved in a number of more aggressive, metastatic varieties of cancer due to its role in cell survival, proliferation and EMT transitioning. Further study of this pathway may lead to new prognostic factors and new drug targets to combat more aggressive forms of cancer.

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Section: Overview Of Mapksmentioning

confidence: 99%

Section: Inhibitors Of Mek5/erk5mentioning

confidence: 99%

MEK5/ERK5 pathway: The first fifteen years

Drew

Burow

Beckman

2012

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

140

198

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“…For now, there is no data on pharmacokinetics and pharmacodynamics for BIX02188 and BIX02819. In addition, Flaherty et al (59) also produced a series of benzimidazole-based MEK5 inhibitors (no IC 50 data available). Among these small molecule compounds, compound 6 inhibits EGF-induced BMK1 activation, and slows down the growth of MCF-7 breast cancer cells (59).…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

“…In addition, Flaherty et al (59) also produced a series of benzimidazole-based MEK5 inhibitors (no IC 50 data available). Among these small molecule compounds, compound 6 inhibits EGF-induced BMK1 activation, and slows down the growth of MCF-7 breast cancer cells (59). Nevertheless, compound 6 is not specific to MEK5 since it also blocks ERK1/2 activation induced by EGF as well.…”

Section: Clinical-translational Advancesmentioning

confidence: 99%

Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy

Yang

Lee²

2011

Clinical Cancer Research

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The big mitogen activated protein kinase 1 (BMK1) pathway is the most recently discovered and leaststudied mammalian mitogen-activated protein (MAP) kinase cascade, ubiquitously expressed in all types of cancer cells tested so far. Mitogens and oncogenic signals strongly activate this cellular MAP kinase pathway, thereby passing down proliferative, survival, chemoresistance, invasive, and angiogenic signals in tumor cells. Recently, several pharmacologic small molecule inhibitors of this pathway have been developed. Among them, the BMK1 inhibitor XMD8-92 blocks cellular BMK1 activation and significantly suppresses tumor growth in lung and cervical tumor models and is well tolerated in animals. On the other hand, MEK5 inhibitors, BIX02188, BIX02189, and compound 6, suppress cellular MEK5 activity, but no data exist to date on their effectiveness in animals.

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“…There is need for organometallic couplings on the benzimidazole core. As a part of our continuing interest in 6‐hydroxy‐derived 1,4‐disubstituted benzimidazoles , we sought efficient ways to functionalize the 6‐hydroxy substituent of the benzimidazole core to the corresponding 6‐carbon analogues. Carbon–carbon bond forming reactions of sp 3 ‐hybridized organoboranes with sp 2 or aromatic hybridized triflates or bromides have been reported previously by the Molander group .…”

Section: Introductionmentioning

confidence: 99%

Suzuki–Miyaura Cross‐Coupling of Potassium Organoborates with 6‐Sulfonate Benzimidazoles Using Microwave Irradiation

Jain

Flaherty

2013

Journal of Heterocyclic Chem

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This article focuses on the utility of organotrifluoroborate salts as coupling partners for Suzuki–Miyaura cross‐coupling with 4‐nitro‐6‐triflyl benzimidazoles using microwave irradiation. The C–C bond formation at the 6‐position of the electron‐rich 1‐,4‐,6‐trisubstituted benzimidazole core is challenging and was not achievable via Kumada, Negishi, Stille, or Heck coupling strategies. Yields of 37–70% could be obtained via palladium coupling strategies utilizing potassium benzyl trifluoroborates as the organometallic coupling partner.

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Identification of benzimidazole-based inhibitors of the mitogen activated kinase-5 signaling pathway

Cited by 15 publications

References 36 publications

MEK5/ERK5 pathway: The first fifteen years

MEK5/ERK5 pathway: The first fifteen years

Targeting the BMK1 MAP Kinase Pathway in Cancer Therapy

Suzuki–Miyaura Cross‐Coupling of Potassium Organoborates with 6‐Sulfonate Benzimidazoles Using Microwave Irradiation

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