Flavopiridol Inhibits Glycogen Phosphorylase by Binding at the Inhibitor Site

Oikonomakos, Nikos G.; Schnier, Joachim; Zographos, Spyros E.; Skamnaki, V.T.; Tsitsanou, Katerina E.; Johnson, L.N.

doi:10.1074/jbc.m004485200

Cited by 122 publications

(122 citation statements)

References 40 publications

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“…By using an affinity chromatography approach similar to ours, glycogen phosphorylase was recently identified (25, 27) as a major flavopiridol-binding protein. This CDK inhibitor indeed inhibits glycogen phosphorylase by binding to the purineinhibitory site of the enzyme (26,27). This unexpected result suggests that the anti-proliferative (reviewed in Ref.…”

Section: Fig 9 Gwennpaullone-binding Proteins In L Mexicana (A) Anmentioning

confidence: 96%

“…51 and 52) of flavopiridol may be due to inhibition of intracellular mechanisms other than CDK activity. These include inhibition of glycogen phosphorylase (26,27), GSK-3␣/␤ (10), and cytosolic aldehyde dehydrogenase (25) as well as interaction with multidrug resistance protein 1 (53,54). Similarly, an affinity chromatography approach recently allowed us to identify Erk2 as a major intracellular target of the CDK inhibitor purvalanol (24).…”

Section: Fig 9 Gwennpaullone-binding Proteins In L Mexicana (A) Anmentioning

confidence: 99%

“…The matrix is then washed, and the bound proteins are analyzed by SDS-PAGE and identified by microsequencing. This approach has allowed the discovery of several unexpected targets of purvalanol (24) and flavopiridol (25)(26)(27) (see "Discussion").…”

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confidence: 99%

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Intracellular Targets of Paullones

Knockaert¹,

Wieking²,

Schmitt³

et al. 2002

Journal of Biological Chemistry

135

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Numerous inhibitors of cyclin-dependent kinases and glycogen synthase kinase-3 (GSK-3) are being developed in view of their potential applications against cancers and neurodegenerative disorders. Among these, paullones constitute a family of potent and apparently selective cyclin-dependent kinase and GSK-3 inhibitors. However, their actual intracellular targets remain to be identified. To address this issue we have immobilized a paullone, gwennpaullone, on an agarose matrix. Extracts from various cell types and tissues were screened for proteins interacting with this matrix. This approach validated GSK-3␣ and GSK-3␤ as major intracellular paullone targets and also mitochondrial, but not cytoplasmic, malate dehydrogenase (MDH). Mitochondrial MDH was indeed inhibited by micromolar concentrations of paullones. Mitochondrial MDH was the major paullone-binding protein in the parasitic protozoon Leishmania mexicana, and paullones inhibited growth of the parasite. This simple batchwise affinity chromatography approach constitutes a straightforward method for the identification of intracellular targets of this particular class of novel anti-mitotic compounds. It has revealed an unexpected target, mitochondrial MDH, the inhibition of which may participate in the pharmacological effects of paullones.

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Section: Fig 9 Gwennpaullone-binding Proteins In L Mexicana (A) Anmentioning

confidence: 96%

Section: Fig 9 Gwennpaullone-binding Proteins In L Mexicana (A) Anmentioning

confidence: 99%

See 1 more Smart Citation

Intracellular Targets of Paullones

Knockaert¹,

Wieking²,

Schmitt³

et al. 2002

Journal of Biological Chemistry

135

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“…The inhibition is enhanced with glucose decreasing the IC50 ~ 5-fold. This inhibition is very similar to the inhibitory effects of caffeine [23]. The structures of GPa , complexed with both glucose and flavopiridol GPb complexed with flavopiridol, and GPb, with caffeine have been determined and analyzed, to understand binding modes of flavopiridol to GP.…”

Section: Ttrwt Binding Chrysin (Ttrwt_chr) Ttrwt Binding Luteolin (Tmentioning

confidence: 77%

“…Enhanced binding to Tyr613, Glu572, and Lys574 was seen in these docking studies with CPB "derivatives". Potent anti-tumor drugs currently in phase II trails PDB codes 1C8K and 1E1Y: Flavopiridol (L86-8275) ((-)-cis-5,7-dihydroxy-2-(2-chlorophenyl)-8-[4-(3-hydroxy-1-methyl)-piperidinyl]-4H-benzopyran-4-one), currently in phase II trials, is thought to be a potent antitumor drug that inhibits muscle glycogen phosphorylase (GP) [23]. The binding of L86-8275 to GP causes glycogen accumulation in non-small cell lung carcinoma cells (A549) [23].…”

Section: Ttrwt Binding Chrysin (Ttrwt_chr) Ttrwt Binding Luteolin (Tmentioning

confidence: 99%

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

Sosa¹,

Sosa²,

Phansalkar³

et al. 2017

Nat Prod Chem Res

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Plants produce pigments called flavonoids that are synthesized (de novo) primarily from the amino acid phenylalanine. Many natural products such as herb preparations for medicinal use contain flavonoids and so these diverse structural compounds have become potential lead compounds for a variety of illnesses ranging from specific cancers to gout. Recently, Biotechnology has been utilized through bioorganic engineering to manufacture flavonoid and modified flavonoids for medicinal applications. A growing number of protein-flavonoid complexes have been crystallized and their structures solved in the last decade. A summary of the protein-flavonoid complexes with medicinal relevance is presented herein. A detailed analysis of selected protein-flavonoid complexes is provided. The goal is to provide insights for modifications to known flavonoids that could be biomanufactured to generate more specific and efficient binding of flavonoids to protein targets with medicinal relevance.

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Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs

Cimini

Benedetti

D’Angelo

et al. 2016

Journal Cellular Physiology

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Glioblastoma, the most common brain tumor, is characterized by high proliferation rate, invasion, angiogenesis, and chemo- and radio-resistance. One of most remarkable feature of glioblastoma is the switch toward a glycolytic energetic metabolism that leads to high glucose uptake and consumption and a strong production of lactate. Activation of several oncogene pathways like Akt, c-myc, and ras induces glycolysis and angiogenesis and acts to assure glycolysis prosecution, tumor proliferation, and resistance to therapy. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes resulting in an overproduction of pyruvate and lactate. Metabolism of glioblastoma thus represents a key issue for cancer research. Flavopiridol is a synthetic flavonoid that inhibits a wide range of Cyclin-dependent kinase, that has been demonstrate to inactivate glycogen phosphorylase, decreasing glucose availability for glycolysis. In this work the study of glucose metabolism upon flavopiridol treatment in the two different glioblastoma cell lines. The results obtained point towards an effect of flavopiridol in glycolytic cells, thus suggesting a possible new use of this compound or flavopiridol-derived formulations in combination with anti-proliferative agents in glioblastoma patients. J. Cell. Physiol. 232: 312-322, 2017. © 2016 Wiley Periodicals, Inc.

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Flavopiridol Inhibits Glycogen Phosphorylase by Binding at the Inhibitor Site

Abstract: Flavopiridol (L86 -8275) ((؊)Flavopiridol (L86 -8275, Scheme I), a flavonoid, has been shown to be a potent, competitive inhibitor (with respect to

Cited by 122 publications

References 40 publications

Intracellular Targets of Paullones

Intracellular Targets of Paullones

Structural Analysis of Flavonoid/Drug Target Complexes: Natural Products as Lead Compounds for Drug Development

Flavopiridol: An Old Drug With New Perspectives? Implication for Development of New Drugs

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