# US 2014/0194632 A1 · Method for Screening for Compounds Selectively Interacting with RAD9

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- Number: US 2014/0194632 A1
- Document ID: US20140194632A1
- Status: Published application
- Kind: A1
- Application number: 13/959,324
- Filed: 2013-08-05
- Published: 2014-07-10
- Earliest claimed: 2008-10-24
- Assignees: Magnachem International Laboratories, Inc.
- Applicants: Magnachem International Laboratories, Inc.
- Inventors: Federico M. Gomez; C. Federico Gomez Garcia-Godoy; David Terrero
- Web page: https://patentgrep.com/patent/US20140194632A1

## CPC

- A61P 35/00: Antineoplastic agents
- C12Q 1/18: Testing for antimicrobial activity of a material
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 2333/4739: Cyclin; Prad 1
- G01N 2510/00: Detection of programmed cell death, i.e. apoptosis
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Natural and synthetic compounds of Formulae Ia-Ie having a lactone structure, in particular Securolide, have been determined to be effective anti-tumor compounds which target the hrad9 gene and/or protein encoded thereby or complex containing the protein and/or the p53 gene and/or protein. Securolide is cytoselective for mutants of hRad9 based on studies conducted in Rad9 mutant yeast strains. Securolide appears to interact with mutant hRad9 in cancer cells to produce DNA lesions which result in apoptosis. Studies have demonstrated that Securolide is useful for treating proliferation disorders such as melanoma, leukemia, breast cancer, lung cancer, ovarian cancer, colon cancer, esophagus cancer, liver cancer, and lymphatic cancer, and to alleviate pain associated with the cancer. Other compounds effective for the treatment of cancer and optionally pain associated therewith may also be identified using the same assays, for example, by screening for efficacy in assays using Rad9 and/or p53 defective mutant yeasts.

## Claims

### Claim 1

A method for screening for pharmaceutically active compounds comprising
(a) providing cells having one or more mutations in the cell cycle checkpoint protein complex that includes Rad9, or a gene encoding a protein in the complex,
(b) adding a compound to be screened to the cells, and
(c) determining if the compound kills or induces apoptosis in some or all of the cells, and
(d) comparing the resultant determination of step (c) to the resultant determination induced by the compound in normal cells not having the one or more mutations in (a) to determine if the compound has anti-cancer activity.

### Claim 2 (depends on 1)

The method of claim 1 wherein the cells are yeast cells.

### Claim 3 (depends on 1)

The method of claim 1 wherein the cells are mammalian cells.

### Claim 4 (depends on 1)

The method of claim 1 wherein the cells are in an animal.

### Claim 5 (depends on 1)

The method of claim 1 wherein the cells are tumor cells.

### Claim 6 (depends on 1)

The method of claim 1 further comprising adding the compound to normal cells not having a mutation in the cell cycle checkpoint protein complex including Rad9.

### Claim 7 (depends on 1)

The method of claim 1 wherein the cells have a mutation in the Rad9 gene.

### Claim 8 (depends on 1)

The method of claim 1 wherein the cells have an inactive or less active Rad9 protein.

### Claim 9 (depends on 1)

A pharmaceutically acceptable compound identified by the method of claim 1.

### Claim 10

A method for screening for pharmaceutically active compounds comprising
(a) providing cells having one or more mutations in the protein p53, or a gene encoding the protein,
(b) adding a compound to be screened to the cells, and
(c) determining if the compound kills or induces apoptosis in some or all of the cells.

### Claim 11 (depends on 10)

The method of claim 10 wherein the cells are yeast cells.

### Claim 12 (depends on 10)

The method of claim 10 wherein the cells are mammalian cells.

### Claim 13 (depends on 10)

The method of claim 10 wherein the cells are in an animal.

### Claim 14 (depends on 10)

The method of claim 10 wherein the cells are tumor cells.

### Claim 15 (depends on 10)

The method of claim 10 further comprising adding the compound to normal cells not having a mutation in the p53 protein.

### Claim 16 (depends on 10)

The method of claim 10 wherein the cells have a mutation in the p53 gene.

### Claim 17 (depends on 10)

The method of claim 10 wherein the cells have an inactive or less active p53 protein.

### Claim 18 (depends on 10)

A pharmaceutically acceptable compound identified by the method of claim 10.