# US 10,864,248 B2 · Dab2 inhibitors for the prevention and treatment of cystic fibrosis

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- Number: US 10,864,248 B2
- Document ID: US10864248B2
- Status: Granted
- Kind: B2
- Application number: 15/526,392
- Filed: 2015-11-11
- Published: 2017-10-26
- Granted: 2020-12-15
- Earliest claimed: 2014-11-12
- Assignees: Trustees of Dartmouth College
- Applicants: Trustees of Dartmouth College
- Inventors: Dean R. Madden
- Web page: https://patentgrep.com/patent/US10864248B2

## CPC

- A61K 38/10: Peptides having 12 to 20 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 9/007: {Pulmonary tract; Aromatherapy}
- A61K 31/4196: 1,2,4-Triazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/4745: condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines (yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48)
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/56: Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K 31/565: not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/4712: {Cystic fibrosis}
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- 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
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)

## Abstract

Compositions and kits including an agent that inhibits the interaction between Disabled-2 and mutant CFTR proteins, optionally in combination with a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof are provided as are methods for preventing or treating cystic fibrosis.

## Claims

### Claim 1

A peptide for inhibiting the interaction between a degradation-prone Cystic Fibrosis Transmembrane Conductance Regulator and Disabled-2 comprising the amino acid sequence of SEQ ID NO:2.

### Claim 2 (depends on 1)

The peptide of claim 1, wherein the peptide has the amino acid sequence QNGFDNPNYQFFEQMQN (SEQ ID NO:3) or QNGFDNPNPYQPQENMQA (SEQ ID NO:4).

### Claim 3 (depends on 1)

The peptide of claim 1, wherein the peptide is derivatized with a label, one or more post-translational modifications, a cell-penetrating sequence, or a combination thereof.

### Claim 4 (depends on 1)

A pharmaceutical composition comprising the peptide of claim 1 in admixture with a pharmaceutically acceptable carrier.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein the composition is formulated for administration via inhalation.

### Claim 6

A pharmaceutical composition comprising
(i) a pharmaceutically acceptable carrier in admixture with a compound of Formula II, or hydrate, prodrug or pharmaceutically acceptable salt thereof:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; and
R4 is ═O or ═S; and
(ii) a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof.

### Claim 7

A pharmaceutical composition comprising
(i) a pharmaceutically acceptable carrier in admixture with a compound of Formula III, or hydrate, prodrug or pharmaceutically acceptable salt thereof:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3, R4, R5 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; or
R4 together with R3 or R5 form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group;
R7 is a substituted or unsubstituted lower alkyl; and
dashed bonds are independently present or absent; and
(ii) a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof.

### Claim 8 (depends on 6, 7)

The pharmaceutical composition of claim 6 or 7, wherein the composition is formulated for administration via inhalation.

### Claim 9 (depends on 4)

The pharmaceutical composition of claim 4, further comprising a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof.

### Claim 10

A kit comprising
(a) an agent that inhibits the interaction between a degradation-prone Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) and Disabled-2, wherein said agent comprises:
(i) a peptide having the amino acid sequence of SEQ ID NO:2,
(ii) a compound has the structure of Formula II:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; and
R4 is ═O or ═S, or
(iii) a compound has the structure of Formula III:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3, R4, R5 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; or
R4 together with R3 or R5 form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group;
R7 is a substituted or unsubstituted lower alkyl; and
dashed bonds are independently present or absent; and
(b) a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof.

### Claim 11 (depends on 10)

The kit of claim 10, wherein the peptide has the amino acid sequence QNGFDNPNYQFFEQMQN (SEQ ID NO:3) or QNGFDNPNPYQPQENMQA (SEQ ID NO:4).

### Claim 12 (depends on 11)

The kit of claim 11, wherein the peptide is derivatized with a label, one or more post-translational modifications, a cell-penetrating sequence, or a combination thereof.

### Claim 13

A method for treating cystic fibrosis comprising administering to a subject in need thereof a pharmaceutical composition comprising:
(i) a peptide having the amino acid sequence of SEQ ID NO:2,
(ii) a compound has the structure of Formula II:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; and
R4 is ═O or ═S, or
(iii) a compound has the structure of Formula III:
wherein
R1 is present or absent, and when present is a substituent on one or more ring atoms and is for each ring atom independently a hydroxyl group, a halo group, or a substituted or unsubstituted lower alkyl or alkoxy group;
R2, R3, R4, R5 and R6 are independently present or absent and when present independently represent hydrogen or a substituted or unsubstituted lower alkyl; or
R4 together with R3 or R5 form a substituted or unsubstituted cycloalkyl or heterocycloalkyl group;
R7 is a substituted or unsubstituted lower alkyl; and
dashed bonds are independently present or absent, thereby treating the subject's cystic fibrosis.

### Claim 14 (depends on 13)

The method of claim 13, further comprising administering to the subject a CFTR corrector, CFTR potentiator, CAL inhibitor, mucolytic, anti-inflammatory agent or a combination thereof.