# US 2018/0024115 A9 · Screening method

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- Number: US 2018/0024115 A9
- Document ID: US20180024115A9
- Status: Published application
- Kind: A9
- Application number: 15/048,653
- Filed: 2016-02-19
- Published: 2018-01-25
- Earliest claimed: 2013-08-19
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hoffmann-La Roche Inc.
- Inventors: Martin Ebeling; Friedrich Metzger; Manaswini Sivaramakrishnan
- Web page: https://patentgrep.com/patent/US20180024115A9

## CPC

- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575)
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 33/5023: {on expression patterns}
- G01N 33/5073: {Stem cells}
- C12Q 2600/136: Screening for pharmacological compounds
- C12Q 2600/156: Polymorphic or mutational markers
- G01N 2333/4706: stimulating, promoting or activating activity
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- G01N 2500/10: involving cells
- 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
- 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

The invention discloses a screening method for the identification of new compounds for use in the treatment of cancer.

## Claims

### Claim 1

A compound modifying splicing of the FoxM1 gene for use in the prophylaxis or treatment of cancer, wherein the compound induces a transcriptionally inactive FoxM1 variant.

### Claim 2 (depends on 1)

The compound of claim 1, wherein the transcriptionally inactive FoxM1 variant is FoxM1A.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the FoxM1 gene is the human FoxM1 gene.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the cancer is selected from the group consisting of cancer of the liver, prostate, brain, breast, lung, colon, pancreas, skin, cervix, ovary, mouth, blood and nervous system.

### Claim 5 (depends on 1)

The compound of claim 1 having formula I:
wherein R1 is selected from aryl, heteroaryl, heterocycloalkyl, which all three substituents are optionally substituted by C1-7 alkyl, C1-7 alkoxy, C1-7 haloalkoxy, C1-7 haloalkyl, halogen, hydroxyl, cyano, NO2;
R2 is C1-7 alkoxy optionally substituted by heterocycloalkyl, NR′R″, or heterocycloalkyl optionally substituted by hydroxy, NR′R″—C1-7 alkyl, hydroxy-C1-7 alkyl, C3-8 cyclopropyl, heterocycloalkyl, C1-7 alkoxy-C1-7 alkyl, hydroxy-C1-7 alkoxy-C1-7 alkyl, halogen or azaspirocycloalkyl, azabicyloalkyl, C2-7 alkynyl optionally substituted by NR′R″, or heteroaryl optionally substituted by C1-7 alkyl,
R3 is halogen, C1-7 alkyl,
R′ and R″ are independently selected from hydrogen, C1-7 alkyl, hydroxy-C1-7 alkyl.

### Claim 6 (depends on 5)

The compound of claim 5, wherein:
R1 is aryl or heteroaryl both substituents optionally substituted by C1-7 alkyl, C1-7 haloalkyl, halogen, C1-7 alkoxy, NR′R″,
R2 is heteroaryl or heterocycloalkyl both substituents optionally substituted by C1-7 alkyl, hydroxy-C1-7 alkyl, halo-C1-7 alkyl,
R3 is C1-7 alkyl.

### Claim 7 (depends on 5)

The compound of claim 5, wherein:
R1 is phenyl, imidazo[1,2-a]pyrazinyl, pyrazolo[1,5-a]pyrazinyl, imidazo[1,2-a]pyridinyl, 1,3-benzoxazolyl, indazolyl.

### Claim 8 (depends on 5)

The compound of claim 5, wherein R2 is piperidinyl, morpholinyl, piperazinyl, pyridinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolidinyl.

### Claim 9 (depends on 1)

Use of the compound of claim 1 for the preparation of a medicament for the prophylaxis or treatment or of cancer.

### Claim 10 (depends on 1)

A pharmaceutical formulation comprising a compound of claim 1.

### Claim 11 (depends on 1)

A method for the prophylaxis or treatment of cancer comprising administering an effective amount of a compound of claim 1 to a subject.

### Claim 12

A method of screening for compounds for the prophylaxis or treatment of cancer comprising:
c) contacting proliferating cells expressing the FoxM1 gene with a test compound,
d) measuring the FoxM1 variant FoxM1A in the cells of step a), wherein an increased level of the FoxM1A variant compared to a control is indicative for a compound for the prophylaxis or treatment of cancer.

### Claim 13

A method of screening for compounds for the prophylaxis or treatment of cancer comprising:
c) contacting proliferating cells expressing the FoxM1 gene with a test compound,
d) measuring the FoxM1 variant FoxM1B and/or variant FoxM1C in the cells of step a), wherein a decreased level of the variant FoxM1B and/or variant FoxM1C compared to a control is indicative for a compound for the prophylaxis or treatment of cancer.

### Claim 14 (depends on 12)

The method of claim 12, wherein the cells are fibroblasts.

### Claim 15 (depends on 12)

The method of claim 12, wherein the FoxM1 variants are measured on RNA level.

### Claim 16 (depends on 12)

The method of claim 12, wherein the the FoxM1 variants are measured on protein level.

### Claim 17

The invention as described herein before.