# US 2019/0167756 A1 · Foxm1 modulators and uses thereof

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- Number: US 2019/0167756 A1
- Document ID: US20190167756A1
- Status: Published application
- Kind: A1
- Application number: 16/323,032
- Filed: 2017-08-01
- Published: 2019-06-06
- Earliest claimed: 2016-08-04
- Assignees: City of Hope
- Applicants: City of Hope
- Inventors: Jeremy Jones; Maya Otto-Duessel
- Web page: https://patentgrep.com/patent/US20190167756A1

## CPC

- A61K 38/12: Cyclic peptides {, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C (A61K38/043 - A61K38/046 take precedence)}
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 38/1709: {from mammals}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- 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 herein, inter alia, are FOXM1 modulators and methods for modulating the activity of androgen receptors in neuronal cells to treat various diseases, such as spinal-bulbar muscular atrophy, amyotrophic lateral sclerosis, and Alzheimer's disease.

## Claims

### Claim 1

A method of treating spinal-bulbar muscular atrophy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a FOXM1 inhibitor to treat the spinal-bulbar muscular atrophy.

### Claim 2 (depends on 1)

The method of claim 1, wherein the administering comprises contacting a motor neuron of the subject with the FOXM1 inhibitor.

### Claim 3 (depends on 1)

The method of claim 1, wherein the method of treating spinal-bulbar muscular atrophy comprises a method of treating a symptom of spinal-bulbar muscular atrophy.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method of treating spinal-bulbar muscular atrophy comprises delaying the onset of spinal-bulbar muscular atrophy.

### Claim 5

A method of reducing the level of androgen receptor activity in a motor neuron, the method comprising contacting the motor neuron with an effective amount of a FOXM1 inhibitor to reduce the level of androgen receptor activity in the motor neuron.

### Claim 6 (depends on 5)

The method of claim 5, wherein the androgen receptor comprises an expanded polyglutamine tract compared to a wildtype androgen receptor.

### Claim 7

A method of treating an androgen receptor activity-associated disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a FOXM1 inhibitor to treat the androgen receptor activity-associated disease.

### Claim 8 (depends on 7)

The method of claim 7, wherein the androgen receptor activity-associated disease is prostate cancer, benign prostatic hyperplasia, hypersexuality, acne, amenorrhea, seborrhea, hirsutism, androgenic alopecia, hidradenitis suppurativa, spinal-bulbar muscular atrophy, Alzheimer's Disease, amyotrophic lateral sclerosis, or hyperandrogenism.

### Claim 9

A method of treating amyotrophic lateral sclerosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a FOXM1 inhibitor to treat the amyotrophic lateral sclerosis.

### Claim 10

A method of treating Alzheimer's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a FOXM1 inhibitor to treat the Alzheimer's disease.

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is an antibiotic.

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a thiazole antibiotic.

### Claim 13 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is thiostrepton.

### Claim 14 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is siomycin.

### Claim 15 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is FDI-2, FDI-4, FDI-6, FDI-7, FDI-10, or FDI-11; or a pharmaceutically acceptable salt of any one of the foregoing.

### Claim 16 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a substituted FDI-2, a substituted FDI-4, a substituted FDI-6, a substituted FDI-7, a substituted FDI-10, a substituted FDI-11, a substituted thiostrepton, or a substituted siomycin; or a pharmaceutically acceptable salt of any of the foregoing.

### Claim 17 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising a sequence that is at least 80% identical to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18; SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27; SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO: 31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40.

### Claim 18 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising a sequence that is at least 90% identical to SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18; SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27; SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO: 31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40.

### Claim 19 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising SEQ ID NO:5, SEQ ID NO:6, SEQ ID NO:7, SEQ ID NO:8, SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18; SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27; SEQ ID NO:28, SEQ ID NO:29, SEQ ID NO:30, SEQ ID NO: 31, SEQ ID NO:32, SEQ ID NO:33, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO:39, or SEQ ID NO:40.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising a sequence that is at least 80% identical to SEQ ID NO:5.

### Claim 21 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising a sequence that is at least 90% identical to SEQ ID NO:5

### Claim 22 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide comprising SEQ ID NO:5.

### Claim 23 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence at least 80% identical to a portion of human p14ARF protein.

### Claim 24 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence at least 80% identical to a portion of a mouse p19ARF protein.

### Claim 25 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence at least 85% identical to SEQ ID NO:3.

### Claim 26 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence of SEQ ID NO:3.

### Claim 27 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence at least 85% identical to SEQ ID NO:4.

### Claim 28 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10)

The method of any one of claims 1 to 10, wherein the FOXM1 inhibitor is a peptide having a sequence of SEQ ID NO:4.

### Claim 29 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1 to 28, wherein the FOXM1 inhibitor reduces the interaction between FOXM1 and an androgen receptor in a motor neuron.

### Claim 30 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1 to 28, wherein the FOXM1 inhibitor reduces the interaction between FOXM1 and β-catenin in a motor neuron.

### Claim 31 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28)

The method of any one of claims 1 to 28, wherein the FOXM1 inhibitor reduces the level of a complex of FOXM1, androgen receptor, and β-catenin in a motor neuron.

### Claim 32 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31)

The method of any one of claims 1 to 31, wherein the FOXM1 inhibitor selectively inhibits androgen receptor activity in a neuronal cell.

### Claim 33 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32)

The method of any one of claims 1 to 32, wherein the FOXM1 inhibitor selectively inhibits androgen receptor activity in a neuronal cell in comparison to a muscle cell.

### Claim 34

The method of any one of embodiments 1 to 33, wherein the FOXM1 inhibitor does not inhibit androgen receptor activity in a muscle cell.