Rel inhibitors and methods of use thereof
This invention provides REL inhibitors which interfere with the DNA binding capacity of a REL protein. Additionally this invention provides methods of treating, abrogating, or preventing diseases which respond with a positive clinical score to a REL inhibitor. Methods of identifying REL inhibitor based on a REL protein three dimensional model are described.
1. A method of treating, inhibiting or suppressing, or meliorating symptoms associated with multiple sclerosis, arthritis, diabetes, graft rejection, or a combination thereof in a subject, comprising the step of contacting the subject with a composition comprising a selective c-Rel:DNA binding inhibitor wherein said c-Rel DNA binding inhibitor masks the L1 cavity of the c-Rel protein, thereby treating, inhibiting or suppressing, or ameliorating symptoms associated with inflammatory conditions that are multiple sclerosis, arthritis, diabetes, colitis, lupus, autoimmunity, graft rejection, or a combination thereof in the subject, wherein said composition comprises a compound set forth by the structure of formula (CXIX):
wherein R 1 is substituted phenyl or unsubstituted phenyl;
R 2 is
wherein X 1 , X 2 , or X 3 are independently H, halogen, alkyl, CN, COOH, or NH 2 ;
or X 3 forms with the ═N + H 2 a five membered fused ring; or
R 2 forms with ═N + H 2 a five or six substituted or unsubstituted membered ring, or their combination.
2. The method of claim 1 , whereby the inhibitor further inhibits the production of interleukin-2, interferon-gamma, or both.
3. The method of claim 1 , whereby said L1 cavity comprises amino acids; Arg 21, Cys 26, Glu 27, Lys 110, and Lys 111.