Structure Determination of MS-444; a New Myosin Light Chain Kinase Inhibitor.

Aotani, Yumiko; Saitoh, Yutaka

doi:10.7164/antibiotics.48.952

Cited by 16 publications

(12 citation statements)

References 3 publications

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“…MS-444 is produced by gram-positive bacteria Micromonospora and originally characterized as myosin light chain (MLC) kinase inhibitor [22, 23]. Molecular docking between the conserved tandem RNA recognition motif (RRM) domains 1 and 2 that are responsible for ARE-binding activity [24–28] and MS-444 predicted a binding energy of −4.6 kcal/mol with hydrogen bonding within the RRM2 domain at residues Ser 146 and Met 117 with bond lengths of 2.7 Å and 2.5 Å, respectively (Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

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Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

et al. 2016

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Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3′UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic.

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Section: Resultsmentioning

confidence: 99%

“…The effects of MS-444 also were specific to HuR since subcellular localization of endogenous (p38 MAPK, Erk1/2, and Akt) proteins were not impacted (Supplementary Figure S2). Furthermore, MS-444 was not observed to impact myosin light chain (MLC) kinase levels [22, 23] or MAPK signaling up to 100 μM (Supplementary Figure S3B-S3C). …”

Section: Resultsmentioning

confidence: 99%

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

et al. 2016

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“…More importantly, this regulation has a functional role on enzyme activity, since we demonstrate that the synergistically increased NADPH oxidase activity and O 2 •− production induced by AngII plus IL-1β, were abolished by NOX-1 and HuR blockade using pharmacological strategies. Moreover, knockdown approaches were also used because the specificity of ML171 and MS-444 are under debate [21,33]. Since NOX-1 has been described to be responsible for O 2 •− production and redox signaling in pathological conditions including atherosclerosis, diabetes, and hypertension [34,35], a limitation of our study is that we do not provide in vivo models that determine the potential role of HuR/NOX-1 regulation.…”

Section: Discussionmentioning

confidence: 99%

“…The effects of the following inhibitors were analyzed by their addition 30 min (or 4 h in the case of MS-444) before and throughout stimulation: actinomycin D, ML171 and cycloheximide (CHX) (Sigma-Aldrich); U0126, SP600125, SB203580 and LY294002 (Calbiochem, Darmstadt, Germany) and MS-444 (generously provided by Novartis, Basel, Switzerland). MS-444 was originally characterized as myosin light chain kinase inhibitor in the μM-range [21], however the concentrations used in these experiments did not affect myosin light chain phosphorylation induced by AngII+IL-1β or cell viability (Supplementary Figure S1A and B). AngII and IL-1β were dissolved in distilled water; the rest of compounds were dissolved in DMSO.…”

Section: Methodsmentioning

confidence: 99%

Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells

Aguado

Rodrı́guez²,

Manea³

et al. 2016

Journal of Hypertension

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Objective NOX-1 and NOX-4 are key enzymes responsible for reactive oxygen species (ROS) generation in vascular smooth muscle cells (VSMC). The RNA-binding protein HuR is implicated in post-transcriptional regulation of gene expression; however, its role regulating NOX is unknown. We investigated transcriptional and post-transcriptional mechanisms underlying angiotensinII (AngII) and interleukin-1β (IL-1β) regulation of NOX-1 and NOX-4 in VSMC and their implications in cell migration. Methods Rat and human VSMC were stimulated with AngII (0.1 μM) and/or IL-1β (10 ng/mL). NOX-1 and NOX-4 mRNA and protein levels, NOX-1 and NOX-4 promoter and 3′UTR activities, NADPH oxidase activity, ROS production and cell migration were studied. Results IL-1β increased NOX-1 expression, NADPH oxidase activity and ROS production and decreased NOX-4 expression and H2O2 production in VSMC. AngII potentiated the IL-1β-mediated induction of NOX-1 expression, NADPH oxidase activity, ROS production and cell migration. However, AngII did not influence IL-1β-induced NOX-4 down-regulation. AngII+IL-1β interfered with the decay of NOX-1 mRNA and promoted HuR binding to NOX-1 mRNA. Moreover, HuR blockade reduced NOX-1 mRNA stability and AngII+IL-1β-induced NOX-1 mRNA levels. IL-1β decreased NOX-4 expression through a transcriptional mechanism that involved response elements situated in the proximal promoter. AngII and/or IL-1β-induced cell migration were prevented by NOX-1 and HuR blockade and were augmented by NOX-4 overexpression. Conclusion In VSMC HuR-mediated mRNA stabilization is partially responsible for AngII+IL-1β-dependent NOX-1 expression whereas transcriptional mechanisms are involved in decreased NOX-4 expression induced by IL-1β. NOX4 and HuR regulation of NOX-1 contributes to VSMC migration, important in vascular inflammation and remodeling.

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“…Among these compounds, calphostin C (110) showed highest potency. 8.16; 126-128) [112][113][114][115][116], clavilactones A-E (129)(130)(131)(132)(133) [117,118], F-12509A (134) [119,120], stemphone (135), and cochlioquinone A (136) [121][122][123]. 8.15-17; 118-125) [106][107][108][109][110][111], herbimycins A-C (Fig.…”

Section: Benzoquinones (Table 83)mentioning

confidence: 99%

Protein Kinase Inhibitors from Microorganisms

Radhika

Kumar

Nagasree

2015

Studies in Natural Products Chemistry

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Structure Determination of MS-444; a New Myosin Light Chain Kinase Inhibitor.

Abstract: MS-444 is a novel myosin light chain kinase inhibitor, isolated from the culture broth of Micromonospora sp. KY7123. The structure of MS-444 was determined to be 5,8-dihydroxy-3methyl-(9i/)-naphtho[2,3-c]furan-4-one by means of spectral analysis.

Cited by 16 publications

References 3 publications

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis

Hu antigen R is required for NOX-1 but not NOX-4 regulation by inflammatory stimuli in vascular smooth muscle cells

Protein Kinase Inhibitors from Microorganisms

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