# US 11,433,137 B2 · Compounds for treating cancer

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- Number: US 11,433,137 B2
- Document ID: US11433137B2
- Status: Granted
- Kind: B2
- Application number: 16/714,938
- Filed: 2019-12-16
- Published: 2020-07-09
- Granted: 2022-09-06
- Earliest claimed: 2017-01-06
- Assignees: BicycleRD Limited
- Applicants: BicycleRD Limited
- Inventors: Gavin Bennett; Daniel Paul Teufel
- Web page: https://patentgrep.com/patent/US11433137B2

## CPC

- A61K 47/64: Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent (peptidic linkers A61K47/65)
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61P 35/00: Antineoplastic agents
- C07K 7/56: the cyclisation not occurring through 2,4-diamino-butanoic acid
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K 7/50: Cyclic peptides containing at least one abnormal peptide link
- 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

The present invention provides compounds, compositions thereof, and methods of using the same.

## Claims

### Claim 1

A method for treating cancer in a patient in need thereof, comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Bicycle is a polypeptide which is covalently bound to a molecular scaffold such that two or more peptide loops are subtended between attachment points to the scaffold, wherein the polypeptide is:
C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C- (SEQ ID NO: 1) wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V; or
C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5) wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine;
Spacer is
AA1-AA2 is a bivalent moiety comprising at least one citrulline moiety that connects the Spacer moiety with the Linker moiety, wherein each of AA1 and AA2 is an independently selected natural or unnatural amino acid moiety;
Linker is a bivalent spacer moiety that connects AA1-AA2 moiety with the Toxin moiety; and
Toxin is a chemotherapeutic agent.

### Claim 2 (depends on 1)

The method of claim 1, wherein the cancer is MT1-positive cancer.

### Claim 3 (depends on 1)

The method of claim 1, wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasalpharyngeal/laryngeal/oesophageal cancer, ovarian cancer, epithelial cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothlioma, bladder cancer, hepatocellular carcinoma, and prostate cancer.

### Claim 4 (depends on 1)

The method of claim 1, wherein the polypeptide is -C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C-(SEQ ID NO: 1), wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V.

### Claim 5 (depends on 1)

The method of claim 1, wherein the polypeptide is -C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5), wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine.

### Claim 6 (depends on 1)

The method of claim 1, wherein the molecular scaffold is

### Claim 7 (depends on 1)

The method of claim 1, wherein the Bicycle is of formula II′:
wherein:
each of L1, L2, and L3 is independently a C1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —S—, —N(R)—, —C(O)—, —C(O)N(R)—, or —N(R)C(O)—;
each R is independently hydrogen or C1-4 alkyl;
Ring A is a 6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
comprises a polypeptide targeting MT1-MMP, wherein the polypeptide is of SEQ ID NO: 1 or SEQ ID NO: 5; and
indicates the site of attachment to the Spacer.

### Claim 8 (depends on 7)

The method of claim 7, wherein each of L1, L2, and L3 is —CH2—, or each of L1, L2, and L3 is —C(O)CH2CH2—.

### Claim 9 (depends on 7)

The method of claim 7, wherein Ring A is selected from:

### Claim 10 (depends on 7)

The method of claim 7, wherein the Bicycle is:

### Claim 11 (depends on 1)

The method of claim 1, wherein the AA1-AA2 moiety is

### Claim 12 (depends on 1)

The method of claim 1, wherein the Linker moiety is

### Claim 13 (depends on 1)

The method of claim 1, wherein the Toxin is selected from the group consisting of MMAE, MMAF, DM1, DM4, SN38, doxorubicin and a duocarmycin analog.

### Claim 14 (depends on 1)

The method of claim 1, wherein said compound is
or a pharmaceutically acceptable salt thereof.

### Claim 15

A method for treating cancer in a patient in need thereof, comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Bicycle is a polypeptide which is covalently bound to a molecular scaffold such that two or more peptide loops are subtended between attachment points to the scaffold;
Spacer is a bivalent moiety that connects the Bicycle moiety with the AA1-AA2 moiety, which is selected from
AA1-AA2 is a bivalent moiety comprising at least one citrulline moiety that connects the Spacer moiety with the Linker moiety, wherein each of AA1 and AA2 is an independently selected natural or unnatural amino acid moiety;
Linker is a bivalent spacer moiety that connects AA1-AA2 moiety with the Toxin moiety; and
Toxin is a chemotherapeutic agent.

### Claim 16 (depends on 15)

The method of claim 15, wherein the polypeptide is -C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C-(SEQ ID NO: 1) wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V.

### Claim 17 (depends on 15)

The method of claim 15, wherein the polypeptide is -C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5), wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine.

### Claim 18 (depends on 15)

The method of claim 15, wherein the molecular scaffold is

### Claim 19 (depends on 15)

The method of claim 15, wherein the Bicycle is of formula II′:
wherein:
each of L1, L2, and L3 is independently a C1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —S—, —N(R)—, —C(O)—, —C(O)N(R)—, or —N(R)C(O)—;
each R is independently hydrogen or C1-4 alkyl;
Ring A is a 6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
comprises a polypeptide targeting MT1-MMP; and
indicates the site of attachment to the Spacer.

### Claim 20 (depends on 19)

The method of claim 19, wherein each of L1, L2, and L3 is —CH2—, or each of L1, L2, and L3 is —C(O)CH2CH2—.

### Claim 21 (depends on 19)

The method of claim 19, wherein Ring A is selected from:

### Claim 22 (depends on 19)

The method of claim 19, wherein the Bicycle is:

### Claim 23 (depends on 15)

The method of claim 15, wherein the AA1-AA2 moiety is

### Claim 24 (depends on 15)

The method of claim 15, wherein the Linker moiety is

### Claim 25 (depends on 15)

The method of claim 15, wherein the Toxin is selected from the group consisting of MMAE, MMAF, DM1, DM4, SN38, doxorubicin and a duocarmycin analog.

### Claim 26 (depends on 15)

The method of claim 15, wherein the cancer is MT1-positive cancer.

### Claim 27 (depends on 15)

The method of claim 15, wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasalpharyngeal/laryngeal/oesophageal cancer, ovarian cancer, epithelial cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothlioma, bladder cancer, hepatocellular carcinoma, and prostate cancer.

### Claim 28 (depends on 15)

The method of claim 15, wherein said compound is selected from:
or a pharmaceutically acceptable salt thereof.