Rare <i>Streptomyces N</i>-Formyl Amino-salicylamides Inhibit Oncogenic K-Ras

Salim, Angela A.; Cho, Kwang Jin; Tan, Lingxiao; Quezada, Michelle; Lacey, Ernest; Hancock, John F.; Capon, Robert J.

doi:10.1021/ol502376e

Cited by 24 publications

(56 citation statements)

References 26 publications

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“…7 However, the exact mode of action and protein targets remain unclear, and there may still be some interplay between the ER and mitochondria, as GRP-78 has been reported to protect epithelial cells from ATP depletion. 44 Consistent with K-Ras acting as a key molecular switch that regulates cell growth, proliferation, and differentiation, studies have demonstrated that preventing Ras PM localization blocks all oncogenic activity, making this family of compounds promising for treating cancer. 127 5.3.4 Inhibition of K-Ras plasma membrane localization.…”

Section: Down-regulation Of Grp-78mentioning

confidence: 98%

“…5 Spectroscopic data showed its relationship to antimycins A 1 and A 3 and was used to elucidate its structure. 43,44 Several variants of neoantimycins differing in the 3-formamidosalicylate moiety and/or oxidation have also been reported. SNA 15896 (soil, Ibaraki Prefecture, Japan) during screening for immunosuppressants.…”

Section: Antimycin-type Depsipeptides With a 15-membered Macrocyclic mentioning

confidence: 99%

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Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

et al. 2016

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Covering: up to 2016Antimycin-type depsipeptides are a family of natural products with great structural diversity and outstanding biological activities. These compounds have typically been isolated from actinomycetes and are generated from hybrid nonribosomal peptide synthetase (NRPS)-polyketide synthase (PKS) assembly lines. This review covers the literature on the four classes of antimycin-type depsipeptides, which differ by macrolactone ring size, and it discusses the discovery, biosynthesis, chemical synthesis, and biological activities of this family of compounds.

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Section: Down-regulation Of Grp-78mentioning

confidence: 98%

Section: Antimycin-type Depsipeptides With a 15-membered Macrocyclic mentioning

confidence: 99%

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

et al. 2016

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“…Among a set of compounds that displace K-RasG12V but not H-RasG12V from the PM in an HCS (18), we found an oligomycin family and a rare neoantimycin family of Streptomyces-derived molecules and the antidiabetic drug metformin (22)(23)(24)35) (Fig. 1A and B).…”

Section: Ampk Activation Triggers Dissociation Of K-ras From the Pmmentioning

confidence: 99%

“…1A and B). All of these compounds have been reported to inhibit various aspects of mitochondrial function (22)(23)(24)35). Since inhibition of mitochondrial activity depletes cellular ATP levels and activates AMPK (36, 37), we tested whether direct AMPK activation would also mislocalize K-RasG12V.…”

Section: Ampk Activation Triggers Dissociation Of K-ras From the Pmmentioning

confidence: 99%

“…Since PtdSer is an anionic phospholipid that provides much of the electrostatic surface potential to the inner PM, a reduced PtdSer PM content leads to K-Ras dissociation. A second group of compounds includes a diverse set of mitochondrial inhibitors (22)(23)(24) that all triggered activation of the master metabolic kinase, AMPactivated protein kinase (AMPK). In dissecting the molecular mechanism, we identified cyclic GMP (cGMP)-dependent protein kinases (PKGs) regulated by nitric oxide (NO) signaling to be novel K-Ras kinases.…”

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confidence: 99%

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AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2

Cho

Casteel

Prakash

et al. 2016

Molecular and Cellular Biology

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f K-Ras must localize to the plasma membrane and be arrayed in nanoclusters for biological activity. We show here that K-Ras is a substrate for cyclic GMP-dependent protein kinases (PKGs). In intact cells, activated PKG2 selectively colocalizes with K-Ras on the plasma membrane and phosphorylates K-Ras at Ser181 in the C-terminal polybasic domain. K-Ras phosphorylation by PKG2 is triggered by activation of AMP-activated protein kinase (AMPK) and requires endothelial nitric oxide synthase and soluble guanylyl cyclase. Phosphorylated K-Ras reorganizes into distinct nanoclusters that retune the signal output. Phosphorylation acutely enhances K-Ras plasma membrane affinity, but phosphorylated K-Ras is progressively lost from the plasma membrane via endocytic recycling. Concordantly, chronic pharmacological activation of AMPK ¡ PKG2 signaling with mitochondrial inhibitors, nitric oxide, or sildenafil inhibits proliferation of K-Ras-positive non-small cell lung cancer cells. The study shows that K-Ras is a target of a metabolic stress-signaling pathway that can be leveraged to inhibit oncogenic K-Ras function. Ras proteins are small GTPases that regulate important cellular signaling cascades to control cell growth, proliferation, and differentiation (1). The three Ras isoforms, H-, N-, and K-Ras4B (here, K-Ras), are ubiquitously expressed in mammalian cells. Ras proteins must be localized to the inner leaflet of the plasma membrane (PM) by a C-terminal membrane anchor for biological activity. In the case of K-Ras, the anchor comprises a posttranslationally attached C-terminal cysteine farnesyl-methyl ester operating in concert with a polybasic motif of 6 lysine residues (2, 3). Electrostatic interactions between the K-Ras C-terminal polybasic domain and the negatively charged inner leaflet of the PM provide membrane affinity (2, 4-9). Maintenance of K-Ras on the PM also requires the chaperone protein PDE␦ (10). Cytosolic PDE␦ binds K-Ras released from the PM as a result of endocytosis and unloads K-Ras in the perinuclear region in response to Arl2/3 binding, whence K-Ras translocates to the recycling endosome (RE) for redelivery to the PM by vesicular transport (11). Ras proteins on the PM are spatially organized into nanodomains, called nanoclusters, that are required for high-fidelity signal transduction by the Ras/mitogen-activated protein kinase (MAPK) pathway (12-14). Ras GTP nanoclusters contain ϳ6 to 7 Ras proteins, are Ͻ20 nm in diameter, and are exclusive platforms for Raf recruitment and MEK/extracellular signal-regulated kinase (ERK) activation. Perturbation of the spatiotemporal dynamics of Ras nanoclustering disrupts cellular signaling (15, 16).We have used a high-content cell-based screen (HCS) to identify multiple chemical compounds that mislocalize K-Ras from the PM and abrogate K-Ras signal transmission (17,18). One group of compounds disrupts the cellular phosphatidylserine (PtdSer) distribution or PtdSer levels with a consequent reduction in the PtdSer content of the inner leaflet of the PM (18-21)....

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Molecular Networking-Based Screening Led to the Discovery of a Cyclic Heptadepsipeptide from an Endolichenic Xylaria sp.

Luo

Chang

et al. 2022

J. Nat. Prod.

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MS/MS-based molecular networking strain prioritization led to the discovery of a group of cyclic depsipeptides from an endolichenic Xylaria sp. The main component, xylaroamide A (1), was obtained by LC-MS-guided isolation. The planar structure of compound 1 was elucidated via 1D and 2D NMR, as well as MS/MS data. The configurations were fully determined by the combination of advanced Marfey's analysis, partial hydrolysis, Mosher's reaction, and GIAO NMR calculation based on a restricted conformational search. A plausible biosynthetic pathway for xylaroamide A (1) involving a rare trans-acting N-methyltransferase is proposed based on bioinformatics analysis. Xylaroamide A (1) exhibited inhibitory activity against cancer cell lines BT-549 and RKO with IC 50 values of 2.5 and 9.5 μM, respectively.

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Rare Streptomyces N-Formyl Amino-salicylamides Inhibit Oncogenic K-Ras

Cited by 24 publications

References 26 publications

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

Antimycin-type depsipeptides: discovery, biosynthesis, chemical synthesis, and bioactivities

AMPK and Endothelial Nitric Oxide Synthase Signaling Regulates K-Ras Plasma Membrane Interactions via Cyclic GMP-Dependent Protein Kinase 2

Molecular Networking-Based Screening Led to the Discovery of a Cyclic Heptadepsipeptide from an Endolichenic Xylaria sp.

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