# US 10,118,942 B2 · Toll-like receptor 2 ligands and methods of making and using thereof

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- Number: US 10,118,942 B2
- Document ID: US10118942B2
- Status: Granted
- Kind: B2
- Application number: 15/561,230
- Filed: 2016-03-25
- Published: 2018-02-22
- Granted: 2018-11-06
- Earliest claimed: 2015-03-26
- Assignees: H. Lee Moffitt Cancer Center and Research Institute, Inc.; Arizona Board of Regents on Behalf of the University of Arizona; University of South Florida
- Applicants: H. Lee Moffitt Cancer Center and Research Institute, Inc.; The Arizona Board of Regents On Behalf of the University of Arizona; University of South Florida
- Inventors: David L. Morse; Josef Vagner; Mark McLaughlin; Robert Gillies; Amanda Huynh; Michael Doligalski
- Web page: https://patentgrep.com/patent/US10118942B2

## CPC

- C07K 5/081: {the side chain containing O or S as heteroatoms, e.g. Cys, Ser}
- A61K 49/0019: {characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules}
- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61K 49/0052: {Small organic molecules (oligomers, polymers, dendrimers A61K49/0054)}
- A61K 51/0497: {conjugates with a carrier being an organic compounds}
- 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)

## Abstract

Disclosed are monoacylated Toll-like receptor 2 ligands which can be used in both the development of targeted agents for the imaging and treatment of pancreatic cancer as well as other cancers, and as an adjuvant for cancer immunotherapy. The monoacylated compounds disclosed herein have a higher binding affinity for TLR2 relative to a known potent diacylated agonists, but only −½ the bioactivity. Competition of the monoacylated compound with the diacylated compound for binding TLR2 was confirmed. Hence, the reported monoacylated compounds are inhibitors/antagonists of TLR2 activation.

## Claims

### Claim 1

A compound having Formula I-A:
wherein
L is a bond, H, or linker moiety of 1 to 20 atoms; and
R1 is an imaging moiety selected from the group consisting of a UV-Vis moiety, a fluorescent moiety a near-infrared moiety, a luminescent moiety, a phosphorescent moiety, a magnetic spin resonance moiety, a photosensitizing moiety, a photocleavable moiety, a chelating center, a heavy atom, a radioactive isotope, an isotope detectable spin resonance moiety, a paramagnetic moiety, a chromophore, and any combination thereof;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R1 is the fluorescent moiety.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R1 is the radioactive isotope.

### Claim 4 (depends on 1)

The compound of claim 1, having the structure
wherein Eu(DPTA) is Europium chelated with diethylenetriaminepentaacetic acid.

### Claim 5 (depends on 1)

The compound of claim 1, having the structure

### Claim 6 (depends on 1)

A method of treating cancer, comprising administering to a subject a compound of claim 1.

### Claim 7 (depends on 6)

The method of claim 6, wherein the cancer is selected from colorectal cancer, ovarian cancer, lung cancer, melanoma, brain cancer, breast cancer, hepatocellular carcinoma, laryngeal cancer, pancreatic adenocarcinoma, stomach cancer, liver cancer, prostate cancer, acute myeloid leukemia, and gastric cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cancer is pancreatic cancer.

### Claim 9 (depends on 1)

A method of removing a cancer from a region within a subject, comprising administering a compound of claim 1 to the subject, irradiating the region to identify the cancer, and surgically removing the cancer.

### Claim 10 (depends on 9)

The method of claim 9, wherein the compound is
wherein Eu(DPTA) is Europium chelated with diethylenetriaminepentaacetic acid.

### Claim 11 (depends on 9)

The method of claim 9, wherein the compound is

### Claim 12

A compound having the structure