Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors

Han, Sangyoon J.; Zhou, Vicki; Pan, Shifeng; Liu, Yi; Hornsby, Michael; McMullan, Daniel; Klock, Heath E.; Haugen, Justin; Lesley, Scott A.; Gray, Nathanael S.; Caldwell, Jeremy S.; Gu, Xiaoqiong

doi:10.1016/j.bmcl.2005.08.097

Cited by 70 publications

(49 citation statements)

References 38 publications

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“…The attractiveness of MEK as a pharmaceutical target has been enhanced by the discovery of highly selective non-ATP-competitive inhibitors of MEK1/2 (18)(19)(20)(21). Such selectivity is achieved by the interaction of the inhibitor with a hydrophobic pocket in MEK that interferes with subsequent binding and hydrolysis of ATP (10).…”

Section: Discussionmentioning

confidence: 99%

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

Iverson¹,

Larson²,

Lai³

et al. 2009

Cancer Research

169

137

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The RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK pathway provides numerous opportunities for targeted oncology therapeutics. In particular, the MEK enzyme is attractive due to high selectivity for its target ERK and the central role that activated ERK plays in driving cell proliferation. The structural, pharmacologic, and pharmacokinetic properties of RDEA119/BAY 869766, an allosteric MEK inhibitor, are presented. RDEA119/BAY 869766 is selectively bound directly to an allosteric pocket in the MEK1/2 enzymes. This compound is highly efficacious at inhibiting cell proliferation in several tumor cell lines in vitro. In vivo, RDEA119/BAY 869766 exhibits potent activity in xenograft models of melanoma, colon, and epidermal carcinoma. RDEA119/BAY 869766 exhibits complete suppression of ERK phosphorylation at fully efficacious doses in mice. RDEA119/BAY 869766 shows a tissue selectivity that reduces its potential for central nervous system-related side effects. Using pharmacokinetic and pharmacodynamic data, we show that maintaining adequate MEK inhibition throughout the dosing interval is likely more important than achieving high peak levels because greater efficacy was achieved with more frequent but lower dosing. Based on its longer half-life in humans than in mice, RDEA119/BAY 869766 has the potential for use as a once-or twice-daily oral treatment for cancer. RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile.

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Section: Discussionmentioning

confidence: 99%

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

Iverson¹,

Larson²,

Lai³

et al. 2009

Cancer Research

169

137

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“…The discovery of the effects of morlin provides a tool for investigating these questions. Morlin is an analog of a class of bioactive small molecules, the coumarins, that have long been implicated in both the inhibition of cellulose deposition in plants and the inhibition of microtubules in mammalian cells (16)(17)(18)(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

Morlin, an inhibitor of cortical microtubule dynamics and cellulose synthase movement

DeBolt

Gutierrez²,

Ehrhardt³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

147

106

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Morlin (7-ethoxy-4-methyl chromen-2-one) was discovered in a screen of 20,000 compounds for small molecules that cause altered cell morphology resulting in swollen root phenotype in Arabidopsis. Live-cell imaging of fluorescently labeled cellulose synthase (CESA) and microtubules showed that morlin acts on the cortical microtubules and alters the movement of CESA. Morlin caused a novel syndrome of cytoskeletal defects, characterized by cortical array reorientation and compromised rates of both microtubule elongation and shrinking. Formation of shorter and more bundled microtubules and detachment from the cell membrane resulted when GFP::MAP4-MBP was used to visualize microtubules during morlin treatment. Cytoskeletal effects were accompanied by a reduction in the velocity and redistribution of CESA complexes labeled with YFP::CESA6 at the cell cortex. Morlin caused no inhibition of mouse myoblast, bacterial or fungal cell proliferation at concentrations that inhibit plant cell growth. By contrast, morlin stimulated microtubule disassembly in cultured hippocampal neurons but had no significant effect on cell viability. Thus, morlin appears to be a useful new probe of the mechanisms that regulate microtubule cortical array organization and its functional interaction with CESA.Arabidopsis ͉ cell wall ͉ chemical genetics ͉ cytoskeleton

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“…Recently reported coumarin derivatives such as G8935 (6) (Fig. 1), structurally related to 1 and 2 and identified as mitogen activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitors (MEK1 inhibitors), raise the possibility that the coumarin-3-carboxylates 1 and 2 may exert their anti-cancer activity through inhibition of MEK1 [15]. Another recent work showed that coumarin-3-carboxamides (7, Fig.…”

Section: Introductionmentioning

confidence: 99%

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

Kempen

Hemmer

Counerotte

et al. 2008

European Journal of Medicinal Chemistry

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Novel 6-substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives were synthesized and their potency in reducing the invasive behaviour of HT 1080 fibrosarcoma cells was evaluated. Structure-activity relationships were deduced from biological results and will be used in further design of new active compounds. In particular, the acetoxymethyl substituent found at the 6-position of previously described active compounds can be replaced by an acetamidomethyl substituent without loss of potency; while the presence of an aryl ester function at the 3-position was preferred to a thioester or an amide function to induce marked biological activity.This work confirms the interest of aryl esters of 6-substituted coumarin-3-carboxylic acids as potential new anticancer agents.

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Identification of coumarin derivatives as a novel class of allosteric MEK1 inhibitors

Cited by 70 publications

References 38 publications

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

RDEA119/BAY 869766: A Potent, Selective, Allosteric Inhibitor of MEK1/2 for the Treatment of Cancer

Morlin, an inhibitor of cortical microtubule dynamics and cellulose synthase movement

6-Substituted 2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives in a new approach of the treatment of cancer cell invasion and metastasis

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