BVT 948

BVT948 is a noncompetitive, cell-permeable and novel PTP inhibitor with an IC50 of 0.09-1.7 µM. [1]

Protein-tyrosine phosphatases (PTPs) are involved in the regulation of diverse intracellular signalings. It can promote cell migration in mammalian cells [2], induce MMP-9 expression in MCF-7 breast cancer cells. [3]

BVT948 blocks breast cancer cell invasion via suppression of the expression of MMP-9. Treatment of 0.5, 1 or 5 μM BVT948 for 24 h did not cause any significant changes in MCF-7 cell viability. BVT948 inhibited TPA-induced MMP-9 up-regulation in a dose-dependent manner. Treatment MCF-7 cells with BVT948 blocked the up-regulation of TPA-induced MMP-9 protein expression. BVT948 significantly diminished TPA-induced MMP-9 secretion. BVT948 diminished 50% cell invasion after the TPA-induced. BVT948 inhibits NF-κB activation by suppressing IκBα degradation and the nuclear translocation of NF-κB in TPA-treated MCF-7 cells. The MAPK pathways are not involved in the inhibition of TPA-induced MMP-9 expression by BVT948. [4]

References:
1.  Liljebris, C., Baranczewski, P., Björkstrand, E., et al. Oxidation of protein tyrosine phosphatases as a pharmaceutical mechanism of action: A study using 4-hydroxy-3,3-dimethyl-2H-benzo [g]indole-2,5(3H)-dione. J Pharmacol Exp Ther 309(2) 711-719 (2004).
2.  Jallal, B., Mossie, K., Vasiloudis, G., Knyazev, P., Zachwieja, J., Clairvoyant, F., Schilling, J. and Ullrich, A. (1997) The receptor-like protein-tyrosine phosphatase DEP-1 is constitutively associated with a 64-kDa protein serine/threonine kinase. J. Biol. Chem. 272, 12158-12163.
3.  Wang, F. M., Liu, H. Q., Liu, S. R., Tang, S. P., Yang, L. and Feng, G. S. (2005) SHP-2 promoting migration and metastasis of MCF-7 with loss of E-cadherin, dephosphorylation of FAK and secretion of MMP-9 induced by IL-1 beta in vivo and in vitro. Breast Cancer Res. Treat. 89, 5-14.
4.  Hwang BM, Chae HS, Jeong YJ et al.Protein tyrosine phosphatase controls breast cancer invasion through the expression of matrix metalloproteinase-9.BMB Rep. 2013 Nov;46(11):533-8.

Oxidation of protein tyrosine phosphatases as a pharmaceutical mechanism of action: a study using 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione.[Pubmed:14747616]

J Pharmacol Exp Ther. 2004 May;309(2):711-9.

Growth factor and insulin signal transduction comprise series of protein kinases and protein phosphatases whose combined activities serve to propagate the growth factor signal in a regulated fashion. It was shown previously that such signaling cascades generate hydrogen peroxide inside cells. Recent work has implied that one function of this might be to enhance the feed-forward signal through the reversible oxidation and inhibition of protein tyrosine phosphatases (PTPs). We identified compound 4-hydroxy-3,3-dimethyl-2H-benzo[g]indole-2,5(3H)-dione (BVT.948) as an agent that is able to inhibit PTP activity in vitro noncompetitively, a mechanism involving oxidation of the catalytic cysteine residue. We investigated the pharmaceutical utility of this compound by examining its effects in a series of in vitro cellular and in vivo assays. Results showed that BVT.948 was able to enhance insulin signaling in cells, although it did not increase tyrosine phosphorylation globally. Furthermore, the compound was active in vivo, enhancing insulin tolerance tests in ob/ob mice, therefore apparently enhancing insulin sensitivity. BVT.948 was able to inhibit several other PTPs tested and also was efficient at inhibiting several cytochrome P450 (P450) isoforms in vitro. The data suggest that inhibitors of PTPs that display noncompetitive kinetics must be viewed with caution because they may oxidize the enzyme irreversibly. Furthermore, although such compounds display interesting biological effects in vitro and in vivo, their general pharmaceutical utility may be limited due to undesired effects on P450 enzymes.

Protein tyrosine phosphatase controls breast cancer invasion through the expression of matrix metalloproteinase-9.[Pubmed:24152909]

BMB Rep. 2013 Nov;46(11):533-8.

The expression of matrix metalloproteinases (MMPs) produced by cancer cells has been associated with the high potential of metastasis in several human carcinomas, including breast cancer. Several pieces of evidence demonstrate that protein tyrosine phosphatases (PTP) have functions that promote cell migration and metastasis in breast cancer. We analyzed whether PTP inhibitor might control breast cancer invasion through MMP expression. Herein, we investigate the effect of 4-hydroxy-3,3-dimethyl-2H benzo[g]indole-2,5(3H)-dione (BVT948), a novel PTP inhibitor, on 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced MMP-9 expression and cell invasion in MCF-7 cells. The expression of MMP-9 and cell invasion increased after TPA treatment, whereas TPA-induced MMP-9 expression and cell invasion were decreased by BVT948 pretreatment. Also, BVT948 suppressed NF-kappaB activation in TPA-treated MCF-7 cells. However, BVT948 didn't block TPA-induced AP-1 activation in MCF-7 cells. Our results suggest that the PTP inhibitor blocks breast cancer invasion via suppression of the expression of MMP-9.

BVT948 is a protein tyrosine phosphatase (PTP) inhibitor which can also inhibit several cytochrome P450 (P450) isoforms and lysine methyltransferase SETD8 (KMT5A).

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