# US 11,440,939 B2 · Anticancer peptides

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- Number: US 11,440,939 B2
- Document ID: US11440939B2
- Status: Granted
- Kind: B2
- Application number: 16/634,067
- Filed: 2018-07-24
- Published: 2021-07-29
- Granted: 2022-09-13
- Earliest claimed: 2017-07-25
- Assignees: Idp Discovery Pharma, S.L.
- Applicants: Idp Discovery Pharma, S.L.
- Inventors: Santiago Esteban Martín; Laura Nevola; Fernando Lecanda Cordero; Haritz Moreno Moreno
- Web page: https://patentgrep.com/patent/US11440939B2

## CPC

- C07K 7/08: having 12 to 20 amino acids (gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68)
- C07K 14/47: from mammals
- A61K 47/62: the modifying agent being a protein, peptide or polyamino acid
- A61P 35/00: Antineoplastic agents
- 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)
- C07K 2319/00: Fusion polypeptide
- 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)
- 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

The present invention provides a peptide of formula (I) or a pharmaceutical salt thereof wherein “m”, “n”, “p”, and “q” represent integers and are selected from 0 and 1; and “r” is comprised from 1 to 10; a linker biradical of formula (II), which is connecting an alpha carbon atom of an amino acid located at position “i” in the peptide sequence of formula (I) with an alpha carbon atom of an amino acid located at position “i+4” or “i+7” in the peptide sequence of formula (I); a C-terminal end corresponding to —C(O)R4; and a N-terminal end corresponding to —NHR5. The peptides of the invention show anticancer activity and an appropriate half-life and stability. Formula (I).

## Claims

### Claim 1

A peptide of formula (I) or a pharmaceutical salt thereof:
wherein
“m”, “n”, “p”, and “q” represent integers and are selected from 0 and 1; and
“r” is an integer from 1 to 10;
the peptide comprising:
a linker biradical “L” of formula (II)
—[(R1)a—(R2)—(R3)b]c— (II)
which is connecting an alpha carbon atom of an amino acid located at position “i” in the peptide sequence of formula (I) with an alpha carbon atom of an amino acid located at position “i+4” or “i+7” in the peptide sequence of formula (I),
a C-terminal end corresponding to —C(O)R4; and
a N-terminal end corresponding to —NHR5;
wherein,
“a” and “b” are the same or different and are 0 or 1;
“c” is an integer from 1 to 10;
R1 and R3 are biradicals independently selected from the group consisting of: (C1-C10)alkyl; (C1-C10)alkyl substituted by one or more radicals selected from the group consisting of: halogen, (C1-C10)alkyl, —OR6, —NR7R8, —SR9, —SOR10, —SO2R11, and —CO2R12; (C2-C10)alkenyl; (C2-C10)alkenyl substituted by one or more radicals selected from the group consisting of: halogen, (C1-C10)alkyl, —OR6, —NR7R8, —SR9, —SOR10, —SO2R11, and —CO2R12; (C2-C10)alkynyl; and (C2-C10)alkinyl substituted by one or more radicals selected from the group consisting of: halogen, (C1-C10)alkyl, —OR6, —NR7R8, —SR9, —SOR10, —SO2R11, and —CO2R12;
R2 is a biradical selected from the group consisting of: —O—, C(═O), C(═O)NR13, C(═O)O, S(═O), S(═O)2, NR14, (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, —NR15—NR16—, —N═N—, —S—S—, and a known ring system comprising from 3 to 14 members, the system comprising from 1 to 3 rings, where:
each one of the rings is saturated, partially unsaturated, or aromatic;
the rings are isolated, partially or totally fused,
each one of the members forming the known ring system is selected from the group consisting of:
—CH—, —CH2—, —NH—, —N—, —SH—, —S—, and —O—; and
the ring system is optionally substituted by one or more radicals independently selected from the group consisting of halogen, —OH, —NO2, (C1-C10)alkyl, (C1-C10)haloalkyl, and (C1-C10)alkyl-O—; and
R4 is a radical selected from the group consisting of —OH and —NR17R18;
R5 is a radical selected from the group consisting of —H and (C1-C20)alkyl;
R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17 and R18 are radicals independently selected from the group consisting of: —H and (C1-C10)alkyl; and
the amino acids of the peptide of formula (I) which are connected by the linker biradical “L” are replaced by an amino acid of formula (III)
wherein
R19 is a monoradical selected from the group consisting of: (C1-C10)alkyl, (C2-C10)alkenyl, (C2-C10)alkynyl, and a known ring system comprising from 3 to 14 members, the system comprising from 1 to 3 rings, where:
each one of the rings is saturated, partially unsaturated, or aromatic;
the rings are isolated, partially or totally fused,
each one of the members forming the known ring system is selected from the group consisting of: —CH—, —CH2—, —NH—, —N—, —SH—, —S—, and —O—;
or, alternatively, a peptide or pharmaceutical acceptable salt thereof having an identity of at least 85% with the peptide of sequence SEQ ID NO: 18
wherein
L is a linker biradical of formula (II) as defined above, and
X is an amino acid of formula (III), as defined above.

### Claim 2 (depends on 1)

The peptide according to claim 1 which is one of formula (I) or a pharmaceutical salt thereof:
wherein
“m”, “n”, “p”, “q”, and “r” are as defined in claim 1,
and the peptide comprises a linker biradical of formula (II), a C-terminal end and a N-terminal end as defined in claim 1.

### Claim 3 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein ‘r’, “a”, “b”, and “c” are 1.

### Claim 4 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein R1 and R3 are biradicals independently selected from the group consisting of: (C1-C10)alkyl; (C2-C10)alkenyl; and (C2-C10)alkynyl.

### Claim 5 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein R2 is a biradical selected from the group consisting of: (C1-C10)alkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl.

### Claim 6 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein R19 is a monoradical selected from the group consisting of: (C1-C10)alkyl, (C2-C10)alkenyl, and (C2-C10)alkynyl.

### Claim 7 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein R1, R3 and R19 are (C1-C10)alkyl; R2 is (C2-C10)alkenyl; “m” and “n” are the same; and “p” and “q” are the same.

### Claim 8 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, wherein the C-terminal end corresponds to —C(O)OH or —C(O)NH2, and the N-terminal end corresponds to —NH2.

### Claim 9 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, which is of formula (Ia) or (Ib):
wherein “m”, “n”, “p”, “q”, L, and R19 are as defined in any of the preceding claims.

### Claim 10 (depends on 1)

The peptide or a pharmaceutical salt thereof according to claim 1, which is a peptide or pharmaceutical acceptable salt thereof having an identity of at least 85% with the peptide of sequence SEQ ID NO: 18 and it is selected from the group consisting of: (ibis1), (ibis2), (ibis3), (ibis4), (ibis5) and (ibis6):
wherein AA3 is an amino acid other than Thr, and “X” and “L” are as defined above;
wherein AA4 is an amino acid other than Glu, and “X” and “L” are as defined above;
wherein AA5 is an amino acid other than Pro, and “X” and “L” are as defined above;
wherein AA2 is an amino acid other than Ala, AA3 is an amino acid other than Thr, AA4 is an amino acid other than Glu, and “X” and “L” are as defined above;
wherein AA1 is an amino acid other than Asn, and “X” and “L” are as defined above;
wherein AA2 is an amino acid other than Ala, and “X” and “L” are as defined above.

### Claim 11 (depends on 1)

The peptide according to claim 1, which is selected from the group consisting of SEQ ID NO: 2 to 14.

### Claim 12 (depends on 1)

The peptide according to claim 1, which is conjugated to a label, a drug or, alternatively, to a stabilizing moiety.

### Claim 13 (depends on 12)

The peptide according to claim 12, which is of sequence SEQ ID NO: 16.

### Claim 14 (depends on 1)

A fusion protein comprising the peptide or pharmaceutical acceptable salt thereof as defined in claim 1 and, optionally, a cell penetrating peptide.

### Claim 15 (depends on 14)

The fusion protein according to claim 14, which is of sequence SEQ ID NO: 17.

### Claim 16 (depends on 1)

A pharmaceutical composition comprising a therapeutically effective amount of the peptide or a pharmaceutical salt thereof of claim 1, together with acceptable pharmaceutical excipients and/or carriers.

### Claim 17 (depends on 1)

A method of treating cancer, wherein the cancer is selected from the group consisting of leukemia, breast cancer, glioblastoma, and lung cancer, the method comprising administering a therapeutically effective amount of the peptide or a pharmaceutical salt thereof of claim 1 to a subject in need thereof.

### Claim 18 (depends on 14)

A method of treating cancer, wherein the cancer is selected from the group consisting of leukemia, breast cancer, glioblastoma, and lung cancer, the method comprising administering a therapeutically effective amount of the fusion protein of claim 14 to a subject in need thereof.

### Claim 19 (depends on 16)

A method of treating cancer, wherein the cancer is selected from the group consisting of leukemia, breast cancer, glioblastoma, and lung cancer, the method comprising administering a therapeutically effective amount of the pharmaceutical composition of claim 16 to a subject in need thereof.

### Claim 20 (depends on 17)

The method of claim 17, wherein therapeutically effective amount of the peptide or a pharmaceutical salt thereof is administered in combination with one or more anti-cancer agents.