Dual inhibitors of farnesyltransferase and geranylgeranyltransferase I
Many GTPases such as Ras, Ral and Rho require post-translational farnestylation or geranylgeranylation for mediating malignant transformation. Dual farnesyltransferase (FT) (FTI) and geranylgeranyltransferase-I (GGT-1) inhibitors (GGTI) were developed as anticancer agents from based on an ethylenediamine scaffold. On the basis of a 4-fold substituted ethylenediamine scaffold, the inhibitors are structurally simple and readily derivatized, facilitating extensive structure-activity relationship studies. The most potent inhibitor is compound exhibited an in vitro hFTase IC 50 value of 25 nM and a whole cell H-Ras processing IC 50 value of 90 nM. Several of the inhibitors proved highly selective for hFTase over the related prenyltransferase enzyme geranylgeranyltransferase-I (GGTase-I). A crystal structure of an inhibitor cocrystallized with farnesyl pyrophosphate in the active site of rat FTase illustrates that the para-benzonitrile moiety is stabilized by a π-π stacking interaction with the Y361β residue, suggesting an importance of this component of the inhibitors.
1. A composition, wherein the composition further comprises a compound of the general formula:
wherein R 1 is
wherein R 2 is
wherein R 3 is
wherein R 1 , R 2 , and R 3 are not concurrently:
R 1 is
and R 2 is
and
R 1 is
R 2 is
and R 3 is
2. The composition of claim 1 , wherein R 1 is
3. The composition of claim 1 , wherein R 1 is
4. The composition of claim 1 , wherein R 1 is
5. The composition of claim 1 , wherein R 1 is
6. The composition of claim 2 , wherein the composition further comprises a compound of the formula:
7. A method of treating cancer comprising administering a compound having the general formula:
wherein R 1 is
wherein R 2 is
wherein R 3 is
wherein R 1 , R 2 , and R 3 are not concurrently:
R 1 is
and R 2 is
R 1 is
R 2 is
and
where the cancer is pancreatic cancer, colonic cancer, lung cancer, or breast cancer.
8. The method of claim 7 , wherein R 1 is
9. The method of claim 7 , wherein R 1 is
10. The method of claim 7 , wherein R 1 is
11. The method of claim 7 , wherein R 1 is
12. The method of claim 8 , wherein the composition further comprises the formula:
13. The method of claim 7 , wherein the compound is administered at 50-100 mg/kg daily.
14. The method of claim 13 , wherein the compound is administration orally or intravenously.