Specific inhibitors of NFAT activation by calcineurin and their use in treating immune-related diseases
First Claim
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1. A pharmaceutical composition comprising a therapeutically effective amount of an organic molecule capable of inhibiting protein-protein interaction between calcineurin and NFAT, and a pharmaceutically acceptable carrier.
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Abstract
Isolated peptide fragments of the conserved regulatory domain of NFAT protein capable of inhibiting protein-protein interaction between calcineurin and NFAT, or a biologically active analog thereof are described. Isolated polynucleotides and gene therapy vectors encoding such peptide fragments are also described. In addition, methods for treating immune-related diseases or conditions and methods for high throughput screening of candidate agents are described. Pharmaceutical compositions are also provided.
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Citations
23 Claims
- 1. A pharmaceutical composition comprising a therapeutically effective amount of an organic molecule capable of inhibiting protein-protein interaction between calcineurin and NFAT, and a pharmaceutically acceptable carrier.
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18. A process of making an agent that inhibits protein-protein interaction between calcineurin and NFAT, the process comprising:
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carrying out a method to identify an agent that inhibits protein-protein interaction between calcineurin and NFAT, wherein the method comprises;
providing a first compound selected from the group consisting of calcineurin or a biologically active derivative thereof, and NFAT or a biologically active derivative thereof;
providing a second compound selected from the group consisting of calcineurin or a biologically active derivative thereof, and NFAT or a biologically active derivative thereof, wherein the second compound is different from the first compound, and wherein the second compound is labeled;
providing a candidate agent;
contacting the first compound, the second compound, and the candidate agent with each other; and
determining the amount of label bound to the first compound, wherein a reduction in interaction between the first compound and the second compound as assessed by label bound is indicative of usefulness of the candidate agent in inhibiting protein-protein interaction between calcineurin and NFAT; and
manufacturing the agent, to thereby make an agent that inhibits protein-protein interaction between calcineurin and NFAT. - View Dependent Claims (19, 20)
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21. A method of manufacturing an agent that inhibits protein-protein interaction between calcineurin and NFAT, the method comprising:
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providing an organic compound capable of inhibiting protein-protein interaction between calcineurin and NFAT;
providing at least one pharmaceutically acceptable carrier; and
combining the organic compound with the pharmaceutically acceptable carrier, to thereby manufacture an agent that inhibits protein-protein interaction between calcineurin and NFAT. - View Dependent Claims (22)
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23. A method for inhibiting protein-protein interaction between calcineurin and NFAT, comprising:
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providing calcineurin and NFAT;
providing an organic molecule capable of inhibiting protein-protein interaction between calcineurin and NFAT, wherein the organic molecule is a compound selected from the group consisting of;
formula (I);
wherein;
R1 is hydrogen, C1-C20 alkyl optionally substituted with 1-20 R6, C3-C8 cycloalkyl optionally substituted with 1-3 R6, aryl optionally substituted with 1-4 R6, heterocyclyl optionally substituted with 1-3 R6;
heteroaryl optionally substituted with 1-4 R6;
C2-C8 alkenyl, or C2-C8 alkynyl, cyano, nitro, carboxy, carbo(C1-C6)alkoxy, trihalomethyl, halogen, C1-C6 alkoxy, hydroxy, aryloxy, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, or ureido;
R2 is C1-C20 alkyl optionally substituted with 1-20 R6, C3-C8 cycloalkyl optionally substituted with 1-3 R6, aryl optionally substituted with 1-4 R6, heterocyclyl optionally substituted with 1-3 R6, heteroaryl optionally substituted with 1-4 R6, C1-C6 alkoxy, hydroxy;
R3 is hydrogen or halogen;
R4 is hydrogen, C1-C20 alkyl optionally substituted with 1-20 R6, C3-C8 cycloalkyl optionally substituted with 1-3 R6, aryl optionally substituted with 1-4 R6, heterocyclyl optionally substituted with 1-3 R6, heteroaryl optionally substituted with 1-4 R6, or halogen;
R5 is NR7, O or S;
R6 is halogen, hydroxy, oxo, nitro, haloalkyl, alkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, alkyl amino, dialkylamino, aryl amino, diarylamino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, mercapto or ureido; and
R7 is C1-C6 alkyl;
formula (II);
wherein;
R1 and R2 are each independently hydrogen, halogen, amino, C1-C6alkylamino, di(C1-C6)alkylamino, arylamino, diarylamino, or 4,4-dimethyl-2,6-dioxocyclohexyl;
R3 is NR11 or O;
R4, R5 and R8 are each independently hydrogen, C1-C6 alkyl, halogen, hydroxy, nitro, haloalkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, alkyl amino, dialkylamino, aryl amino, diarylamino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, mercapto or ureido;
R6 is hydrogen, halogen, or when taken together with R7 forms a double bond between the carbon atoms to which they are attached;
R7 is hydrogen, halogen, or when taken together with R6 forms a double bond between the carbon atoms to which they are attached;
R9 is OR13, or when taken together with R10 forms a double bond between the carbon and nitrogen atoms to which they are attached;
R10 is hydrogen, or when taken together with R9 forms a double bond between the carbon and nitrogen atoms to which they are attached;
R11 is SO2R12; and
R12 is aryl optionally substituted with alkyl;
R13 is alkyl or aryl; and
formula (III);
wherein, R1 and R4 are each independently O or NR8;
R2 and R3 are each independently hydrogen, halogen, or R2 and R3 together combine to form aryl optionally substituted with 1-4 R9;
R5 is hydrogen, halogen, carboxy, acylamino, alkoxycarbonyl, carboxy, alkylcarbonyl, acyloxy, or cyano;
R6, R7 and R9 are each independently hydrogen, C1-C6 alkyl, halogen, hydroxy, nitro, haloalkyl, alkaryl, aryl, aralkyl, alkoxy, aryloxy, amino, alkyl amino, dialkylamino, aryl amino, diarylamino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, alkoxycarbonyl, carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido, arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, mercapto or ureido;
R8 is SO2R10; and
R10 is aryl optionally substituted with alkyl; and
contacting the calcineurin, NFAT, and organic molecule together such that protein-protein interaction between the calcineurin and the NFAT is inhibited.
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Specification