Protein kinase and phosphatase inhibitors and methods for designing them
AssigneeThe Research Foundation of State University of New York
InventorsDavid G. Hangauer JR., Moustafa E. El-Araby, Karen L. Milkiewicz
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Abstract
The present invention provides a method for identifying inhibitors of protein kinases and/or protein phosphatases. Methods are also provided for inhibiting protein kinase and/or protein phosphatase activity. Specific non-peptide protein tyrosine kinase and/or protein phosphatase inhibitors are provided. The protein kinase or protein phosphatase inhibitors of the present invention may be used to treat a number of conditions in patients, including cancer, psoriasis, arthrosclerosis, immune system activity, Type II diabetes, and obesity.
Claims179
A non-peptide protein tyrosine kinase inhibitor or protein phosphatase inhibitor having the formula:
- 429
- wherein X is a halogen;
- R1 through R6 may be the same or different, and are selected from the group consisting of H, C(O)Ra, C(O)NRaRb, C(O)ORa, C(O)SRa, OH, ORa, OC(O)Ra, OC(O)ORa, NH2, NRaRb, NRaC(O)Rb, NRaC(O)NRbRc, NRaC(O)ORb, NRaC(O)SRb, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)ORb, NRaS(O)2ORb, NRaP(O)ORbORc, NRaP(O)ORbRc, NRaP(O)ORbORc, SRa, S(O)Ra, S(O)2Ra, S(O)ORa, S(O)2ORa, S(O)NRaRb, S(O)2NRaRb, P(O)ORaORb, B(OH)2, halogen, aryl, heteroaryl, biaryl, heterobiaryl, heterocyclic compound, and a branched, cyclic, or unbranched alkyl;
- wherein Ra, Rb, and Rc may be the same or different and are selected from the group consisting of H, aryl, heteroaryl, biaryl, heterobiaryl, and branched, cyclic, or unbranched alkyl;
- or
- R5 and R6 together form a heterocyclic compound;
- and
- wherein any of R1 through R6 and Ra through Rc is substituted or unsubstituted.
A non-peptide protein tyrosine kinase inhibitor or protein phosphatase inhibitor having the formula:
- 432
- wherein X is a halogen, R1 is H, R2 is
- 433
- R3 is H, and R4 is H.
A method for identifying inhibitors of protein kinases comprising:
- providing at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein at least one of the one or more functional groups is a halogen;
- combining the at least one first module with at least one second module which provides a non-peptide scaffold to form one or more combinations of the first and second modules;
- screening the one or more combinations of the first and second modules for protein kinase inhibition;
- and
- selecting combinations of the first and second modules which inhibit protein kinase activity.
A method of inhibiting a protein kinase comprising:
- contacting the protein kinase with a compound comprising at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein the one or more functional groups comprise a halogen, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits the protein kinase's activity.
A method of treating a condition, responsive to a protein kinase inhibitor, in a subject comprising:
- administering an effective dose of a protein kinase inhibitor to a subject wherein the protein kinase inhibitor comprises at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein kinase, wherein the one or more functional groups comprise a halogen, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits protein kinase activity.
A method for identifying inhibitors of protein phosphatases comprising:
- providing at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase;
- combining the at least one first module with at least one second module which provides a non-peptide scaffold to form one or more combinations of the first and second modules;
- screening the one or more combinations of the first and second modules for protein phosphatase inhibition;
- and
- selecting combinations of the first and second modules which inhibit protein phosphatase activity.
A method of inhibiting a protein phosphatase comprising:
- contacting the protein phosphatase with a compound comprising at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits the protein phosphatase's activity.
A method of treating a condition, responsive to a protein phosphatase inhibitor, in a subject comprising:
- administering an effective dose of a protein phosphatase inhibitor to a subject wherein the protein phosphatase inhibitor comprises at least one first module having one or more functional groups each capable of covalently or non-covalently binding to catalytic residues of the protein phosphatase, and a second module which provides a non-peptide scaffold, wherein the combination of the at least one first module and second module inhibits protein phosphatase activity.
Dependencies are inferred from the claim text.