# US 2015/0147291 A1 · Zinc Chelating Agents for Depleting Xiap and Sensitizing Tumor Cells to Apoptosis

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- Number: US 2015/0147291 A1
- Document ID: US20150147291A1
- Status: Published application
- Kind: A1
- Application number: 14/610,044
- Filed: 2015-01-30
- Published: 2015-05-28
- Earliest claimed: 2012-07-30
- Assignees: Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center
- Applicants: Institute for Cancer Research d/b/a The Research Institute of Fox Chase Cancer Center
- Inventors: Alexander Kutikov; Vladimir Kolenko; Seth M. Cohen; Robert G. Uzzo; Ervin Teper
- Web page: https://patentgrep.com/patent/US20150147291A1

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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

The invention provides zinc chelating agents and formulations thereof that deplete XIAP in cancer cells and sensitize the cells to apoptosis-inducing agents. The invention provides methods for sensitizing apoptosis-resistant cancer cells to apoptosis-inducing agents, as well as methods for treating a subject with a combined therapy of a zinc chelating agent and an apoptosis-inducing agent.

## Claims

### Claim 1

A method for inducing apoptosis in an apoptosis-resistant cell, comprising contacting an apoptosis-resistant cell with a compound selected from the group consisting of Formula I,
Formula II,
Formula V,
wherein X1 is H, Cl, or F and X2 is CN or F, and a pharmaceutically acceptable salt thereof, in an amount of effective to deplete X-linked inhibitor of apoptosis protein (XIAP) in the cell, and contacting the cell with an amount of an apoptosis-inducing agent effective to induce apoptosis in the cell.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is Formula I,
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound is Formula II,
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

The method of claim 1, wherein the compound is Formula V,
wherein X1 is H, Cl, or F and X2 is CN or F, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The method of claim 4, wherein X1 is Cl and X2 is F.

### Claim 6 (depends on 1)

The method of claim 1, wherein the apoptosis-inducing agent is TNF-related apoptosis-inducing ligand (TRAIL).

### Claim 7 (depends on 1)

The method of claim 1, wherein the cell is a tumor cell.

### Claim 8 (depends on 7)

The method of claim 7, wherein the tumor cell is a prostate tumor cell.

### Claim 9 (depends on 8)

The method of claim 8, wherein the prostate tumor cell is a castration resistant prostate tumor cell.

### Claim 10 (depends on 1)

The method of claim 1, wherein the compound substantially depletes XIAP in the cell.

### Claim 11

A method for treating a tumor, comprising administering to a subject in need thereof a compound selected from the group consisting of Formula I,
Formula II,
Formula V,
wherein X1 is H, Cl, or F and X2 is CN or F, and a pharmaceutically acceptable salt thereof, in an amount of effective to deplete X-linked inhibitor of apoptosis protein (XIAP) XIAP in cells of the tumor, and administering to the subject an apoptosis-inducing agent in an amount of effective to induce apoptosis in cells of the tumor in which XIAP has been depleted, thereby treating the tumor.

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound is Formula I,
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 11)

The method of claim 11, wherein the compound is Formula II,
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 11)

The method of claim 11, wherein the compound is Formula V,
wherein X1 is H, Cl, or F and X2 is CN or F, or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein X1 is Cl and X2 is F.

### Claim 16 (depends on 11)

The method of claim 11, wherein the apoptosis-inducing agent is TNF-related apoptosis-inducing ligand (TRAIL).

### Claim 17 (depends on 11)

The method of claim 11, wherein the tumor is an apoptosis-resistant tumor.

### Claim 18 (depends on 11)

The method of claim 11, wherein the tumor is a tumor of the prostate gland.

### Claim 19 (depends on 18)

The method of claim 18, wherein the tumor of the prostate gland is a castration resistant tumor of the prostate gland.

### Claim 20 (depends on 11)

The method of claim 11, wherein the compound substantially depletes XIAP in cells of the tumor.