INHIBITORS OF ANTIGEN RECEPTOR-INDUCED NF-kappa B ACTIVATION
A method to identify selective inhibitors of antigen receptor-mediated NF-κB activation is provided, as well as compositions having one or more of those inhibitors and methods of using those inhibitors.
1 . A compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.
2 . The compound of claim 1 , wherein R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
3 . The compound of claim 1 , wherein R 2 and R 3 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
4 . The compound of claim 1 , wherein R 9a and R 9b are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
5 . The compound of claim 1 , wherein R 5 -R 8 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
6 . The compound of claim 1 , wherein R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ; wherein R 20 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, and phenyl.
7 . The compound of claim 1 , wherein R 4 is selected from the group consisting of —OH, —OCH 3 , and —OPh.
8 . The compound of claim 1 , wherein R 5 and R 8 are hydrogen.
9 . The compound of claim 1 , wherein R 6 and R 7 are methyl.
10 . The compound of claim 1 , wherein R 10 and R 14 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
11 . The compound of claim 1 , wherein R 11 and R 13 are each independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, and t-butyl.
12 . The compound of claim 1 , wherein R 12 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , methyl, ethyl, propyl, n-butyl, and t-butyl, wherein R 20 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, n-butyl, t-butyl, and phenyl.
13 . The compound of claim 1 , wherein n is an integer between 1-5.
14 . The compound of claim 1 , wherein the compound has the structure:
15 . A pharmaceutical composition comprising a compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.
16 . A method of identifying a compound that selectively inhibits antigen receptor-mediated NF-κB activation comprising:
(a) providing an aqueous solution comprising a cell transfected with a reporter gene driven by a NF-κB responsive promoter;
(b) adding to the solution a test compound;
(c) adding to the solution an NF-κB inducing stimulus; and
(d) determining whether the test compound reduces the cell response to the stimulus;
wherein the test compound is a compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.
17 . The method of claim 16 , wherein the reporter gene is a luciferase reporter gene driven by a NF-κB responsive promoter.
18 . The method of claim 16 , wherein the test compound reduces the response to the stimulus by greater than 50 percent.
19 . A method of selectively inhibiting antigen receptor-mediated NF-κB activation in a cell comprising contacting the cell with a compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.
20 . The method of claim 30 , wherein the contacting is in vivo or in vitro.
21 . A method of selectively inhibiting antigen receptor-mediated NF-κB activation in a subject comprising identifying a subject in need thereof and administering to the subject, or contacting the subject with, a compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.
22 . A method of treating a disease associated with antigen receptor-mediated NF-κB activation in a subject comprising
identifying a subject in need thereof and administering to the subject, or contacting the subject with, a compound of Formula I or Formula II
or a pharmaceutically acceptable salt or prodrug thereof, where
R 1 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 2 , R 3 , R 9a , and R 9b are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl;
R 4 is selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , and —C(O)R 20 ;
R 5 -R 8 and R 10 -R 14 are each independently selected from the group consisting of hydrogen, —OR 20 , —SR 20 , —C(O)OR 20 , —C(O)R 20 , alkyl, cycloalkyl, and aryl;
R 20 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, and aryl; and
n is an integer between 0-10.