# US 11,306,124 B2 · Agonist agents of CD47 inducing programmed cell death and their use in the treatments of diseases associated with defects in programmed cell death

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- Number: US 11,306,124 B2
- Document ID: US11306124B2
- Status: Granted
- Kind: B2
- Application number: 16/099,997
- Filed: 2017-05-10
- Published: 2019-05-09
- Granted: 2022-04-19
- Earliest claimed: 2016-05-10
- Assignees: Sorbonne Universite; Centre National De La Recherche Scientifique
- Applicants: Sorbonne Universite; Centre National de la Recherche Scientifique
- Inventors: Philippe Karoyan
- Web page: https://patentgrep.com/patent/US11306124B2

## CPC

- C07K 7/50: Cyclic peptides containing at least one abnormal peptide link
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 7/64: Cyclic peptides containing only normal peptide links
- C07K 14/4705: {stimulating, promoting or activating activity}
- C07K 14/70596: {Molecules with a "CD"-designation not provided for elsewhere}
- 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: 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention relates to cyclic peptides mimetics of the C-terminal binding domain of TSP-1. The present invention also relates to the use of these cyclic peptides as agonists of CD47 and their ability to trigger programmed cell death (PCD). The present invention further relate to a pharmaceutical composition for use in the treatment of diseases associated with defects in PCD such as cancers and immunological disorders (including chronic inflammation) and comprising at least one cyclic peptide according to the invention.

## Claims

### Claim 1

An isolated cyclic peptide of general formula (Ia):
or a pharmacologically acceptable salt thereof, wherein:
Z1 is nothing or an heterochiral sequence D-Pro-L-Pro or any sequence of two amino acids or analogs of amino acid able to mimic said heterochiral sequence or mimic a beta turn;
B2 represents the peptidic sequence X1-X2-X3-X4-X5-X6-X7-X8-X9-X10 (SEQ ID NO: 2) and comprises between 6 and 10 amino acids, wherein:
X1 refers to nothing or serine;
X2 refers to nothing, arginine, or N-methyl arginine;
X3 refers to phenylalanine;
X4 refers to tyrosine;
X5 refers to valine;
X6 refers to valine;
X7 refers to methionine, lysine, or norleucine;
X8 refers to tryptophan;
X9 refers to nothing or lysine;
X10 refers to nothing or glutamine;
Z2 is nothing or an heterochiral sequence D-Pro-L-Pro or any sequence of two amino acids or analogs of amino acid able to mimic said heterochiral sequence or mimic a beta turn;
B3 is a peptidic sequence of between 6 and 10 amino acids comprising the following sequence: -X19-X14-X15-X20-X21-X16-X22-X23-X17-X18- (SEQ ID NO: 36) wherein:
X14 is nothing, glycine, alanine, or serine;
X15 is isoleucine or leucine;
X16 is lysine or alanine;
X17 is nothing, asparagine, alanine, glutamine or lysine;
X18 is nothing, serine, or glycine;
X19 is nothing or serine;
X20 is serine, alanine or leucine;
X21 is valine or alanine;
X22 is valine; and
X23 is valine or alanine;
wherein said isolated cyclic peptide comprises an even number of amino acids and wherein said isolated cyclic peptide comprises between 8 and 26 amino acids.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising the isolated cyclic peptide of claim 1 and a pharmaceutically acceptable carrier.

### Claim 3 (depends on 1)

The isolated cyclic peptide according to claim 1, wherein both Z1 and Z2 are nothing.

### Claim 4 (depends on 1)

The isolated cyclic peptide according to claim 1, wherein Z1 or Z2 is D-Pro-L-Pro.

### Claim 5 (depends on 1)

A method of treating a disease associated with defects in PCD in a subject in need thereof comprising administering a therapeutically effective amount of the isolated cyclic peptide of claim 1 to the subject.

### Claim 6 (depends on 5)

The method of claim 5, wherein the disease is cancer selected from the group consisting of adrenal cortical cancer, anal cancer, bile duct cancer, multiple myeloma, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, Castleman disease, cervical cancer, colorectal cancer, endometrial cancer, esophagus cancer, gallbladder cancer, gastrointestinal carcinoid tumors, Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, leukemia, liver cancer, lung cancer, mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, melanoma, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, vaginal cancer, vulvar cancer, and uterine cancer.

### Claim 7 (depends on 5)

The method of claim 5, wherein the disease is an immunological disorder.

### Claim 8 (depends on 5)

The method of claim 5, wherein the disease is chronic inflammation.

### Claim 9 (depends on 1)

The isolated cyclic peptide according to the claim 1 wherein said peptide is selected from a group consisting of PKTD1 (SEQ ID NO: 9), PKTD10 (SEQ ID NO: 17), PKTD10-1 (SEQ ID NO: 18), PKTD10-3 (SEQ ID NO: 20), PKTD10-4 (SEQ ID NO: 21), PKTD10-5 (SEQ ID NO: 22), PKTD10-7 (SEQ ID NO: 24), PKTD10-8 (SEQ ID NO: 25), PKTD12 (SEQ ID NO: 29), PKTD18 (SEQ ID NO: 35), PKD8 (SEQ ID NO: 41), PKD9 (SEQ ID NO: 43), PKD10 (SEQ ID NO: 44), PKTD10-RNMe (SEQ ID NO: 54), PKTD10-X-RNMe (SEQ ID NO: 55), PKTD11-RNMe (SEQ ID NO: 60).