US 7,070,936 B1Granted

Method for designing protein kinase inhibitors

AssigneeThe Research Foundation of State University of New York

InventorsDavid G. Hangauer, Jr., Thomas H. Marsilje, Karen L. Milkiewicz

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Abstract

The present invention provides a method for identifying inhibitors of protein kinases. Methods are also provided for inhibiting protein kinase activity. Specific non-peptide protein tyrosine kinase inhibitor are provided. The protein kinases produced using the method of the present invention may be used to treat a number of conditions in patients, including cancer, psoriasis, arthrosclerosis, or immune system activity.

Claims24

Dependent claims

A method for identifying an inhibitor of a protein kinase comprising:

a) providing a first reagent consisting of a peptide scaffold, wherein said peptide scaffold is a substrate for the protein kinase, covalently linked to a first module comprising one or more functional groups selected from the group consisting of boronic acid, a hydroxyl group, phosphonic acid, sulfamic acid, a guanidino group, a carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid;
b) bringing into contact the first reagent, a protein kinase, and a natural substrate for the kinase under conditions sufficient to allow phosphorylation of the substrate;
c) determining the level of phosphorylation of the substrate in the presence of the first reagent and comparing said level to the level of phosphorylation in the absence of the first reagent;
d) selecting the first reagent that has a lower level of substrate phosphorylation in the presence of the first reagent relative to the level of phosphorylation of the substrate in the absence of the first reagent;
e) providing a second reagent consisting of a second module comprising a non-protein scaffold functional group selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene, covalently linked to the first module of the first reagent selected in step d);
f) bringing into contact the second reagent, a protein kinase, and a natural substrate for the kinase under conditions sufficient to allow phosphorylation of the substrate;
g) determining the level of phosphorylation of the substrate in the presence of the second reagent and comparing said level to the level of phosphorylation in the absence of the second reagent;
h) selecting the second reagent that has a lower level of substrate phosphorylation in the presence of the second reagent relative to the level of phosphorylation of the substrate in the absence of the second reagent,
thereby identifying a protein kinase inhibitor.

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Dependencies are inferred from the claim text.

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Abstract

A method for identifying an inhibitor of a protein kinase comprising:

a) providing a first reagent consisting of a peptide scaffold, wherein said peptide scaffold is a substrate for the protein kinase, covalently linked to a first module comprising one or more functional groups selected from the group consisting of boronic acid, a hydroxyl group, phosphonic acid, sulfamic acid, a guanidino group, a carboxylic acid, an aldehyde, an amide, and hydroxymethylphosphonic acid;
b) bringing into contact the first reagent, a protein kinase, and a natural substrate for the kinase under conditions sufficient to allow phosphorylation of the substrate;
c) determining the level of phosphorylation of the substrate in the presence of the first reagent and comparing said level to the level of phosphorylation in the absence of the first reagent;
d) selecting the first reagent that has a lower level of substrate phosphorylation in the presence of the first reagent relative to the level of phosphorylation of the substrate in the absence of the first reagent;
e) providing a second reagent consisting of a second module comprising a non-protein scaffold functional group selected from the group consisting of indole, naphthalene, biphenyl, isoquinoline, benzofuran, and benzothiophene, covalently linked to the first module of the first reagent selected in step d);
f) bringing into contact the second reagent, a protein kinase, and a natural substrate for the kinase under conditions sufficient to allow phosphorylation of the substrate;
g) determining the level of phosphorylation of the substrate in the presence of the second reagent and comparing said level to the level of phosphorylation in the absence of the second reagent;
h) selecting the second reagent that has a lower level of substrate phosphorylation in the presence of the second reagent relative to the level of phosphorylation of the substrate in the absence of the second reagent,
thereby identifying a protein kinase inhibitor.

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