US 5,846,998 A · Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine kinase activators for controlling cellular proliferation

Abstract

A method of inhibiting the proliferation of B cells by using inhibitors of phosphotyrosine phosphatase can be used to regulate the immune response and to treat diseases such as leukemias or lymphomas marked by malignant proliferation of B cells or T cells. Antitumor activity is seen in vivo against tumors and against tumor cell lines. The use o such inhibitors can be combined with radiation, which produces a synergistic effect. Several types of inhibitors can be used, including: (1) compounds comprising a metal coordinate-covalently bound to an organic moiety that can form a five- or six-membered ring, in which the metal is preferably vanadium (IV); (2) compounds in which vanadium (IV) is coordinate-covalently bound to an organic moiety such as a hydroxamate, .alpha.-hydroxypyridinone, .alpha.-hydroxypyrone, .alpha.-amino acid, hydroxycarbonyl, or thiohydroxamate; (3) coordinate-covalent complexes of cysteine or a derivative thereof; (4) nonhydrolyzable phosphotyrosine analogues; (5) dephostatin; (6) 4-(fluoromethyl)phenyl phosphate and esterified derivatives; and (7) coordinate-covalent metal-organic compounds containing at least one oxo or peroxo ligand bound to the metal, in which the metal is preferably vanadium (V), molybdenum (VI), or tungsten (VI).

Claims9

Dependent claims

A method for inhibiting proliferation of a cell type selected from the group consisting of B cells, T cells, and cells derived from malignant transformation of B cells or T cells, comprising the step of contacting proliferating cells selected from the group consisting of B cells, T cells, and cells derived from malignant transformation of B cells or T cells with a coordinate-covalent complex including:

(a) a vanadium (V) metal ion;
(b) an oxo group coordinate-covalently bound to the metal ion;
(c) two peroxo groups coordinate-covalently bound to the metal ion;
and
(d) at least one organic moiety coordinate-covalently bound to the metal ion through at least one N- or O-containing functional group capable of donating electrons through a coordinate-covalent bond, the coordinate-covalent complex having an affinity for the active site of a phosphotyrosine phosphatase sufficient to detectably inhibit the activity of one or more phosphotyrosine phosphatases, wherein the coordinate-covalent complex is selected from the group consisting of (1,10-phenanthroline) oxodiperoxovanadium (V), oxalatooxodiperoxovanadium (V), (2,2'-bipyridine) oxodiperoxovandium (V), (4,7-dimethyl-1,10-phenanthroline)oxodiperoxovanadium (V), (3,4,7,8-tetramethyl-1,10-phenanthroline) oxodiperoxovanadium (V), (pyridine-2-carboxylic acid) oxodiperoxovanadium (V), (pyridine-2,6-dicarboxylic acid) oxodiperoxovanadium (V), and derivatives thereof possessing substantially equivalent affinity for the active site of phosphotyrosine phosphatase.

2 more elements

Dependencies are inferred from the claim text.

Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine kinase activators for controlling cellular proliferation

Life of this patent

Use of phosphotyrosine phosphatase inhibitors or phosphotyrosine kinase activators for controlling cellular proliferation

Life of this patent

Abstract

Claims9