# US 9,040,585 B2 · Small molecule antagonists of phosphatidylinositol-3,4,5-triphosphate (PIP3) and uses thereof

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- Number: US 9,040,585 B2
- Document ID: US9040585B2
- Status: Granted
- Kind: B2
- Application number: 14/103,412
- Filed: 2013-12-11
- Published: 2014-07-03
- Granted: 2015-05-26
- Earliest claimed: 2010-05-18
- Assignees: Tufts University; Council of Scientific and Industrial Research
- Applicants: Tufts University; Council of Scientific and Industrial Research
- Inventors: Alexei Degterev; Chepuri Venkata Ramana; Benchun Miao
- Web page: https://patentgrep.com/patent/US9040585B2

## CPC

- C07C 335/26: Y being a hydrogen or a carbon atom, e.g. benzoylthioureas
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61P 35/00: Antineoplastic agents
- C07C 275/54: Y being a carbon atom of a six-membered aromatic ring, e.g. benzoylureas
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are new members of a class of non-lipid small molecule inhibitors which interfere with the interaction between phosphoinositol-3,4,5-triphosphate (PIP3) and pleckstrin homology (PH) domains. These molecules target a broad range of PIP3-dependent signaling events in vitro and exert significant anti-tumor activity in vivo, with improved activity and selectivity toward particular PH domains. The small molecule inhibitors of the invention can be used alone or together with tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) or other cancer medicament to treat cancer. Small molecule inhibitors of the invention act synergistically in combination with TRAIL and with other Akt inhibitors in treating cancer. Pharmaceutical compositions and methods for treating cancer are provided.

## Claims

### Claim 1

A method of selectively inhibiting a phosphoinositol-3,4,5-triphosphate (PIP3)-dependent cellular signaling pathway in a cell, comprising contacting a cell expressing PIP3 with an effective amount of a compound of Formula II
wherein
R1 and R2 are independently selected from H and —CH3,
R3 and R5 are independently selected from H, —CH3, and —CF3,
R4 is selected from H, —CF3, phenyl, Cl, and Br,
R6 is H,
R7 is OH, and
X is S,
to reduce binding of PIP3 to pleckstrin homology domain, thereby selectively inhibiting the PIP3-dependent cellular signaling pathway in the cell.

### Claim 2 (depends on 1)

The method of claim 1, wherein R4 is phenyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein
R1, R2, R3, and R5 are each —CH3, and
R4 is selected from Cl and Br.

### Claim 4 (depends on 1)

The method of claim 1, wherein
R1 and R2 are each —CH3,
R3 and R5 are each H, and
R4 is —CF3.

### Claim 5 (depends on 1)

The method of claim 1, wherein
R1 and R2 are each —CH3,
R3 and R5 are each —CF3, and
R4 is H.

### Claim 6 (depends on 1)

The method of claim 1, wherein
R1 and R2 are each —CH3,
R3 and R5 are each H, and
R4 is phenyl.

### Claim 7

A method of treating cancer, comprising administering to a subject having a cancer an effective amount of a compound of Formula II
wherein
R1 and R2 are independently selected from H and —CH3,
R3 and R5 are independently selected from H, —CH3, and —CF3,
R4 is selected from H, —CF3, phenyl, Cl, and Br,
R6 is H,
R7 is OH,
X is S, and
the cancer is selected from the group consisting of melanoma, lung cancer, breast cancer, and brain cancer,
thereby treating the cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein R4 is phenyl.

### Claim 9 (depends on 7)

The method of claim 7, wherein
R1, R2, R3, and R5 are each —CH3, and
R4 is selected from Cl and Br.

### Claim 10 (depends on 7)

The method of claim 7, wherein
R1 and R2 are each —CH3,
R3 and R5 are each H, and
R4 is —CF3.

### Claim 11 (depends on 7)

The method of claim 7, wherein
R1 and R2 are each —CH3,
R3 and R5 are each —CF3, and
R4 is H.

### Claim 12 (depends on 7)

The method of claim 7, wherein
R1 and R2 are each —CH3,
R3 and R5 are each H, and
R4 is phenyl.