4-HYDROXY-3,3-DIMETHYL-2H-BENZO[G]INDOLE-2,5(3H)-DIONE

Description

BVT 948 is a noncompetitive, cell-permeable inhibitor of protein tyrosine phosphatases (PTP; IC₅₀s = 0.09-1.7 μM). It facilitates the oxidation of the catalytic cysteine residue by hydrogen peroxide. Similarly, it inhibits redox-sensitive cytochrome P450 (CYP) isoforms, including CYP2C19 and CYP2D6, with IC₅₀ values less than 10 μM. BVT 948 also inhibits the protein methyltransferases SETD8, SETD2, G9a, SMYD2, CARM1, and PRMT3 with IC₅₀ values from 0.7 to 3.2 μm. Presumably through its effects on PTPs, BVT 948 enhances insulin signaling in cells and insulin tolerance in ob/ob mice, suppresses the expression of matrix metalloproteinase-9 and invasion in breast cancer cells, and increases NMDA-induced substance P release by spinal cord slices.

Uses

BVT-948 is a noncompetitive cell-permeable inhibitor of tyrosine phosphatases. Helps in the oxidation of the catalytic cysteine residue. May be used as an anti-cancer treatment.

Biological Activity

Non-competitive, cell-permeable inhibitor of protein tyrosine phosphatases (PTPs) (IC 50 = 0.09-1.7 μ M); displays irreversible inhibition through catalysis of the hydrogen peroxide-dependent oxidation of PTP. Enhances insulin signaling in vitro and insulin tolerance in ob/ob mice in vivo . Also inhibits several cytochrome P450 isoforms (IC 50 < 10 μ M).

in vivo

IC 50

SETD8/KMT5A

storage

Room temperature

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.