# US 9,040,563 B2 · Dual inhibitors of farnesyltransferase and geranylgeranyltransferase I

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- Number: US 9,040,563 B2
- Document ID: US9040563B2
- Status: Granted
- Kind: B2
- Application number: 13/792,900
- Filed: 2013-03-11
- Published: 2013-07-25
- Granted: 2015-05-26
- Earliest claimed: 2010-09-09
- Assignees: H. Lee Moffitt Cancer Center and Research Institute, Inc.; Yale University
- Applicants: H. Lee Moffitt Cancer Center and Research Institute, Inc.; Yale University
- Inventors: Said M. Sebti; Andrew Hamilton
- Web page: https://patentgrep.com/patent/US9040563B2

## CPC

- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- A61K 31/095: Sulfur, selenium, or tellurium compounds, e.g. thiols
- A61K 31/10: Sulfides; Sulfoxides; Sulfones
- A61K 31/4164: 1,3-Diazoles
- A61K 31/417: Imidazole-alkylamines, e.g. histamine, phentolamine
- A61K 31/66: Phosphorus compounds
- C07D 233/84: Sulfur atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 409/14: containing three or more hetero rings
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

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 IC50 value of 25 nM and a whole cell H-Ras processing IC50 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.

## Claims

### Claim 1

A composition, wherein the composition further comprises a compound of the general formula:
wherein R1 is
wherein R2 is
wherein R3 is
wherein R1, R2, and R3 are not concurrently:
R1 is
and R2 is
and
R1 is
R2 is
and R3 is

### Claim 2 (depends on 1)

The composition of claim 1, wherein R1 is

### Claim 3 (depends on 1)

The composition of claim 1, wherein R1 is

### Claim 4 (depends on 1)

The composition of claim 1, wherein R1 is

### Claim 5 (depends on 1)

The composition of claim 1, wherein R1 is

### Claim 6 (depends on 2)

The composition of claim 2, wherein the composition further comprises a compound of the formula:

### Claim 7

A method of treating cancer comprising administering a compound having the general formula:
wherein R1 is
wherein R2 is
wherein R3 is
wherein R1, R2, and R3 are not concurrently:
R1 is
and R2 is
R1 is
R2 is
and
where the cancer is pancreatic cancer, colonic cancer, lung cancer, or breast cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein R1 is

### Claim 9 (depends on 7)

The method of claim 7, wherein R1 is

### Claim 10 (depends on 7)

The method of claim 7, wherein R1 is

### Claim 11 (depends on 7)

The method of claim 7, wherein R1 is

### Claim 12 (depends on 8)

The method of claim 8, wherein the composition further comprises the formula:

### Claim 13 (depends on 7)

The method of claim 7, wherein the compound is administered at 50-100 mg/kg daily.

### Claim 14 (depends on 13)

The method of claim 13, wherein the compound is administration orally or intravenously.