Inhibitors of protein prenyltransferases
The present invention is directed to novel compounds. These compounds can be useful in inhibiting the activity of protein prenyltransferases including GGTase I and/or RabGGTase. The compounds can also be used as anti-cancer therapeutics including as part of methods for treating cancer, in assays, and in kits.
1. A compound having the formula
wherein J is hydrogen or is 1-2 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, OR′, SR′, and NR′2, where R′ is alkyl,
wherein G is
wherein E is hydrogen or is 1-2 substituents selected from the group consisting of halogen, C1-C3 alkyl, OR′, SR′, and NR′2, where R′ is alkyl,
wherein W is selected from the group consisting of hydrogen, cyclic, linear, or branched alkyl of from 2 to 8 carbons, unsubstituted phenyl, and phenyl substituted with C1-C3 alkyl, halogen, OR′, SR′, and NR′2, where R′ is alkyl,
wherein
is selected from the group consisting of
wherein A is selected from the group consisting of:
wherein M is selected from the group consisting of OH, OR″, NH2, NHOH, NHOR″, wherein R″ is methyl or ethyl, or any other group that has a polar metal binder
wherein R corresponds to an alpha-substituent of natural or non-natural alpha-amino acid;
wherein Z is S—U; and
wherein U is selected from the group consisting of alkyl having 10 or fewer carbons, phenyl, optionally substituted with halogen or OR″, wherein R″ is methyl or ethyl, and (CH2)n-COOR4, wherein n=1-4 and R4 is a linear or branched alkyl having four or fewer carbons; or the compound P61-A7
2. A compound of claim 1 , wherein A is
3. A compound of claim 1 , wherein A is
4. A compound of claim 1 , wherein A is
5. The compound of claim 1 , wherein M is OEt, OMe, Ot-Bu, OH, NH2, NHOH, NHOMe, or any other groups that have a polar metal binder.
6. The compound of claim 1 , wherein the compound is selected from the group consisting of
7. The compound of claim 1 , wherein G is
8. The compound of claim 1 , wherein the compound inhibits the activity of a protein prenyltransferase.
9. The compound of claim 1 , wherein the compound inhibits the activity of a RabGGTase.
10. The compound of claim 1 , wherein the compound inhibits the activity of GGTase I.
11. The compound of claim 1 , wherein the compound inhibits the activity of GGTase I and RabGGTase.
12. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
13. A method comprising administering the compound of claim 1 to a cell in an amount sufficient to inhibit the activity of GGTase I and/or RabGGTase.
14. The method of claim 13 , wherein the compound is administered at a micromolar concentration.
15. A method comprising administering a compound of claim 1 in an amount sufficient to inhibit the growth of a cancer cell or to reduce the size of a tumor of cancer cells.
16. The method of claim 15 , wherein the cancer cell comprises GGTase I and/or RabGGTase modified proteins.
17. A method comprising administering to a subject in need of treatment for a cancer the pharmaceutical composition of claim 12 in an amount sufficient to inhibit the activity of a protein prenyltransferase.
18. The method of claim 17 , wherein the protein prenyltransferase is GGTase I, RabGGTase, or both.
19. The method of claim 17 , wherein the cancer cell comprises GGTase I and/or RabGGTase modified proteins.
20. A method comprising measuring the GGTase I and/or RabGGTase inhibiting activity of a compound of claim 1 .
21. A method of preparing a compound according to formula I
wherein:
wherein J is hydrogen or is 1-2 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, OR′, SR′, and NR′2, where R′ is alkyl,
wherein W is selected from the group consisting of hydrogen, cyclic, linear, or branched alkyl of from 2 to 8 carbons, unsubstituted phenyl, and phenyl substituted with C1-C3 alkyl, halogen, OR′, SR′, and NR12, where R′ is alkyl,
G is
wherein E is hydrogen or is 1-2 substituents selected from the group consisting of halogen, C1-C3 alkyl, OR′, SR′, and NR′2, where R′ is alkyl,
is selected from the group consisting of
wherein A is
and M=OH, OR, or NH2; and R is, an alpha-substituent of a natural or non-natural amino acid;
comprising,
reacting a compound according to formula I′
wherein
J, G, and W are as defined above and
is selected from the group consisting of
wherein A=CO2H;
with a compound having the formula
wherein R and M are as defined above.
22. The pharmaceutical composition of claim 12 , wherein the pharmaceutically acceptable carrier or diluent comprises a liposome.
23. A pharmaceutical composition comprising the compound of claim 2 and a pharmaceutically acceptable carrier or diluent.
24. The pharmaceutical composition of claim 23 , wherein the pharmaceutically acceptable carrier or diluent comprises a liposome.
25. A pharmaceutical composition comprising the compound of claim 3 and a pharmaceutically acceptable carrier or diluent.
26. The pharmaceutical composition of claim 25 , wherein the pharmaceutically acceptable carrier or diluent comprises a liposome.
27. A pharmaceutical composition comprising the compound of claim 4 and a pharmaceutically acceptable carrier or diluent.
28. The pharmaceutical composition of claim 27 , wherein the pharmaceutically acceptable carrier or diluent comprises a liposome.
29. A pharmaceutical composition comprising the compound of claim 6 and a pharmaceutically acceptable carrier or diluent.
30. The pharmaceutical composition of claim 29 , wherein the pharmaceutically acceptable carrier or diluent comprises a liposome.