Methods and compositions for modulating P300/CBP activity
The present invention relates to a method for identifying compounds that modulate the activity of p300/CBP. Compounds of the invention are identified by designing or screening for a compound which binds to at least one amino acid residue of the newly identified lysine-CoA inhibitor binding site, L1 loop, electronegative pocket, or electronegative groove of the HAT domain of p300/CBP and testing the compound for its ability to modulate the activity of p300/CBP. Compositions and methods for preventing or treating diseases or disorders associated with p300/CBP are also provided as is a method for producing a semi-synthetic HAT domain.
1. A method for treating breast cancer, ovarian cancer, or melanoma in a subject, comprising administering to a subject in need thereof an effective amount of a p300/CBP inhibitor having the structure of
wherein
the dotted line represents an optional bond,
R 1 is H, NO 2 , or unsubstituted C 1-4 alkyl;
R 2 and R 3 are independently H, CH 3 , or NO 2 ; and
R 4 and R 5 are independently H, NO 2 , SO 3 H, halogen, COOH, CONH 2 , COCH 2 NH 2 , COOCH 3 , COOC 2 H 5 or unsubstituted C 1-4 alkyl.
2. The method of claim 1 , wherein the p300/CBP inhibitor is selected from the group of: