RK‐682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at G<sub>1</sub>phase

Hamaguchi, Takuya; Sudo, Tatsuhiko; Osada, Hiroyuki

doi:10.1016/0014-5793(95)00953-7

Cited by 148 publications

(103 citation statements)

References 23 publications

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“…Since, RNA interference-mediated downregulation of VHR reduces proliferation and arrests these tumor cell lines at the G 1 /S and G 2 /M transitions, 106 it seems logical to assume that specific VHR inhibitors would do the same. Indeed, the tetronic acid derivative RK-682, which was developed as a VHR-specific inhibitor, 119 arrests cells in G 1 /S. We have begun a drug discovery effort and currently have a series of VHR-selective inhibitors with low nanomolar IC 50 values, which are now evaluated for their effects in MAPK and cell cycle progression.…”

Section: Vhr As a Drug Target?mentioning

confidence: 99%

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Cerignoli¹,

Rahmouni²,

Ronai³

et al. 2006

Cell Cycle

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Section: Vhr As a Drug Target?mentioning

confidence: 99%

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Cerignoli¹,

Rahmouni²,

Ronai³

et al. 2006

Cell Cycle

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“…38) The validity of the in vitro assay test was established by testing the inhibitory action of the standard inhibitor RK-682 on h-PTP 1B which showed about 20% activity of the uninhibited phosphatase control when the standard inhibitor RK-682 was used at a final concentration of 100 mM. 35) Furthermore, papaverine decreased fasting blood glucose of Balb/c mice after single intraperitoneal injection. Figure 6 shows that papaverine significantly decreased fasting blood glucose when papaverine was administered at two dose levels (6, 18 mg/kg) normalized to mice weight compared to control group as concluded from multiple comparisons statistical analysis (Tukey's test).…”

Section: Resultsmentioning

confidence: 99%

“…88-682. 32,33,35) The color was allowed to develop at room temperature for 30 min, and the sample absorbance was determined at 630 nm using a plate reader (Bio-Tek instruments ELx 800, U.S.A.). Samples and blanks were prepared in duplicates.…”

Section: Measurement Of H-ptp 1b Inhibitionmentioning

confidence: 99%

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Bustanji

Taha

Almasri

et al. 2009

Biological & Pharmaceutical Bulletin

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Natural products have played an important role in treating and preventing human diseases.1) An analysis of the origin of the drugs that were launched in the last twenty-five years showed that both natural products and semi-synthetic compounds, derived from natural origin, comprised 34% of all new chemical entities, while 18% of them were synthetic mimics of natural compounds.2) Therefore, natural products are considered important sources for new drugs or lead optimization.2,3) The structural diversity of natural products combined with the fact that they were elaborated within living systems render them more "drug-like" than totally synthetic molecules. 4-7)Papaverine (Fig. 1A) is a prominent member of isoquinoline alkaloids isolated from opium poppy (Papaver somniferum L.).8) It exhibits non-selective smooth muscle relaxant effects, which prompted its widespread clinical use in the treatment of vasospasmic diseases.9-11) Papaverine increases the unidirectional K ϩ influx into muscles causing vasodilatation and muscle relaxant effects. The K ϩ flux is associated with increases in glucose uptake which could be one of the causes of hypoglycemia associated with papaverine use. 12)In a recent publication, we revealed a potent inhibitory action for berberine (Fig. 1B), another prominent isoquinoline alkaloid, against the anti-diabetic target human protein tyrosine phosphatase 1B (h-PTP 1B).13) The chemical similarity between berberine and papaverine combined with the fact that they share common biosynthetic origin, 14,15) prompted us to evaluate any possible inhibitory action of papaverine against h-PTP 1B. Furthermore, several reports have indicated that opiates, including papaverine, possess significant hypoglycemic properties. 16,17) The hypoglycemic mechanism of opiates is still uncertain. Furthermore, the hypoglycemic effect of papaverine is not well characterized using in vivo animal models.h-PTP 1B, a cytosolic non-receptor protein tyrosine phosphatase, has been implicated in the progression of diabetes because it acts as negative regulator of insulin signal transduction. h-PTP 1B directly catalyzes the dephosphorylation of cellular substrates of the insulin receptor kinase resulting in a down-regulation of insulin action. [18][19][20][21] Mice lacking functional h-PTP 1B showed enhanced tyrosine kinase activity and increased sensitivity to insulin. 22) In another animalbased approach, treatment with anti-sense oligonucleotide specific for h-PTP 1B resulted in normalization of blood glucose and insulin levels in animal models of type 2 diabetes. 23)Accordingly, h-PTP 1B inhibitors could increase insulin receptor tyrosine phosphorylation, mimic cellular and in vivo actions of insulin, and lower plasma glucose levels in diabetic animal models. [24][25][26][27] The current project commenced by computer-aided docking simulations to probe potential binding interactions within papaverine/h-PTP 1B complex. Subsequently, we validated our theoretical findings in vitro and in vivo. The structural similarity between papa...

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“…Although the natural products dnacin, dysidiolide, a RK-682 analogue and a cholestenone analog appear to inhibit Cdc25 dual speci®city phosphatase (Gunasekera et al, 1996;Hamaguchi et al, 1995;Horiguchi et al, 1994;Peng et al, 1998), there is little information on the nature of their inhibition and selectivity, and these analogs are generally in limited supply. Moreover, the e ects of these compounds on cell cycle transition are not known.…”

Section: Discussionmentioning

confidence: 99%

“…We hypothesized that inhibition of Cdc25A was responsible for the G1 block caused by SC-aad9, as Cdc25A seems to be important for entry into S phase (Hamaguchi et al, 1995;Ho mann et al, 1994;Jinno et al, 1994). The tyrosine phosphorylation status of both Cdk2 and Cdk4 was markedly increased by SCaad9; both of these cyclin-dependent kinases have a central role in regulating the G1 transition (Hunter and Pines, 1994).…”

Section: Discussionmentioning

confidence: 99%

Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

et al. 1999

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The Cdc25 dual speci®city phosphatase family has a central role in controlling cell cycle progression and has been implicated in the etiology of cancer. One compound, 4-(benzyl-(2-[(2, 5-diphenyl-oxazole-4-carbonyl)-amino]-ethyl)-carbamoyl)-2-decanoylamino butyric acid (SC-aad9), was previously identi®ed as the most potent reported synthetic inhibitor of Cdc25 phosphatases in vitro. In the present study, we demonstrate that SC-aad9 inhibited Cdc25-dependent cell cycle progression at both G1 and G2/M phase using tsFT210 cells, which express a temperature-sensitive Cdc2 mutant. SCaad9 blocked both G2/M transition and dephosphorylation of Cdc2 in a concentration-dependent manner. SCaad9 also enhanced tyrosine phosphorylation of both Cdk2 and Cdk4, and decreased Cdk4 kinase activity. Both of the kinases are potent regulators of G1 transition. Furthermore, closely related chemical analogs that lacked Cdc25 inhibitory activity failed to block cell cycle progression at both G1 and G2/M, and did not a ect Cdc2 phosphorylation or Cdk4 kinase activity. SC-aad9 did not alter p53, p21 or p16 levels. Our results support the hypothesis that the disruption in cell cycle transition caused by SC-aad9 was due to intracellular Cdc25 inhibition. We propose that the SC-aad9 pharmacophore could be useful in further clarifying the role of Cdc25 phosphatase-dependent pathways in checkpoint control, oncogenesis, and apoptosis.

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RK‐682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at G₁phase

Cited by 148 publications

References 23 publications

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

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RK‐682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at G1phase

Cited by 148 publications

References 23 publications

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Regulation of MAP Kinases by the VHR Dual-Specific Phosphatase – Implications for Cell Growth and Differentiation

Docking Simulations and in Vitro Assay Unveil Potent Inhibitory Action of Papaverine against Protein Tyrosine Phosphatase 1B

Dual G1 and G2/M phase inhibition by SC-ααδ9, a combinatorially derived Cdc25 phosphatase inhibitor

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RK‐682, a potent inhibitor of tyrosine phosphatase, arrested the mammalian cell cycle progression at G₁phase