Toll-like receptor 2 ligands and methods of making and using thereof

Patent metadata

Field	Value
Publication number	US-10118942-B2
Application number	US-201615561230-A
Country	US
Kind code	B2
Filing date	Mar 25, 2016
Priority date	Mar 26, 2015
Publication date	Nov 6, 2018
Grant date	Nov 6, 2018

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.

First claim

What is claimed is:

1. A compound having Formula I-A:

wherein
L is a bond, H, or linker moiety of 1 to 20 atoms; and
R 1 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.

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

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

4. The compound of claim 1 , having the structure

wherein Eu(DPTA) is Europium chelated with diethylenetriaminepentaacetic acid.

5. The compound of claim 1 , having the structure

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

7. 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.

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

9. 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.

10. The method of claim 9 , wherein the compound is

wherein Eu(DPTA) is Europium chelated with diethylenetriaminepentaacetic acid.

11. The method of claim 9 , wherein the compound is

12. A compound having the structure

Assignees

• H Lee Moffitt Cancer Ct & Res
• Univ Arizona
• Univ South Florida

Inventors

• Morse David L
• Vagner Josef
• Mclaughlin Mark
• Gillies Robert
• Huynh Amanda
• Doligalski Michael

Classifications

• C07K5/081 Primary

  the side chain containing O or S as heteroatoms, e.g. Cys, Ser · CPC title

• A61K49/0052

  Small organic molecules (oligomers, polymers, dendrimers A61K49/0054) · CPC title

• A61K49/0019

  characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules · CPC title

• A61K51/0497

  conjugates with a carrier being an organic compounds · CPC title

• A61K49/0032

  Methine dyes, e.g. cyanine dyes · CPC title