Histone demethylase inhibitors and methods for using the same
View Patent ↗The present invention provides compounds, or derivatives or prodrugs thereof, that comprise a methyllysine mimic, and an α-ketoglutarate mimic that are attached through a linker and methods for using and producing the same. In some embodiments, compounds of the invention are of the formula: M-L-K, or a derivative or a prodrug thereof, wherein M is a methyllysine mimic, L is a linker, and K is an α-ketoglutarate mimic.
1. A compound of the formula: M-L-K, wherein M is a methyllysine mimic, L is a linker, and K is an α-ketoglutarate mimic, wherein the methyllysine mimic is of the formula:
wherein
each of l, m and n is independently 0 or 1;
each of X and Z is independently O, S, or NR 5 ;
Y is O, S or NR 5 ;
R 1 is aryl, aralkyl, heteroaryl or fluorescein;
R 2 is alkylene or a moiety of the formula —R 6 —Ar 1 —R 7 —, wherein each of R 6 and R 7 is independently alkylene, and Ar 1 is arylene;
R 3 is hydrogen, alkyl, aralkyl, heteroalkyl or heteroaralkyl;
R 4 is hydrogen, alkyl, or absent; and
each of R 5 is independently hydrogen or alkyl.
2. The compound according to claim 1 , wherein R 1 is phenyl, naphthyl, benzyl, or naphthylalkyl, each of which is optionally substituted, or fluorescein.
3. The compound according to claim 1 , wherein X is NH.
4. The compound according to claim 1 , wherein Y is O.
5. The compound according to claim 1 , wherein Z is O.
6. The compound according to claim 1 , wherein R 2 is C 3 -C 8 alkylene.
7. The compound according to claim 1 , wherein R 6 and R 7 are methylene.
8. The compound according to claim 1 , wherein Ar 1 is phenylene.
9. The compound according to claim 1 , wherein R 3 is H or methyl.
10. The compound according to claim 1 , wherein R 4 is alkyl or absent.
11. The compound according to claim 1 , wherein the α-ketoglutarate mimic is of the formula:
wherein
Y 1 is OR 8 , or —NHR 8 ;
each of X 1 and X 2 is independently O, S, or NR 9 ;
Y 2 is —OR 8 , —SR 10 , or —NR 11 R 12 ;
each of R 8 is independently hydrogen, alkyl, or a hydroxyl protecting group;
each of R 9 is independently hydrogen, alkyl, or a nitrogen protecting group;
R 10 is hydrogen, alkyl, or a sulfur protecting group;
R 11 is hydrogen or alkyl;
R 12 is hydrogen, alkyl, or a nitrogen protecting group; and
L 1 is alkylene, alkenylene, arene, or alkynylene.
12. The compound according to claim 11 , wherein R 8 is hydrogen or C 1 -C 4 alkyl.
13. The compound according to claim 11 , wherein X 1 and X 2 are O.
14. The compound according to claim 11 , wherein Y 2 is —OR 8 .
15. The compound according to claim 11 , wherein L 1 is C 2 -C 6 alkylene or C 2 -C 6 alkenylene.
16. A composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.