Integrin interaction inhibitors for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10059740-B2
Application number	US-201615165687-A
Country	US
Kind code	B2
Filing date	May 26, 2016
Priority date	Mar 19, 2010
Publication date	Aug 28, 2018
Grant date	Aug 28, 2018

Abstract

Integrin interaction inhibitors using a beta-turn promoter are described herein. These peptides are useful in treating cancer, such as multiple myeloma, by administering a therapeutically effective amount of the integrin interaction inhibitor. Data show that integrin interaction inhibitors act synergistically or additively interact with anti-proliferative agents such as doxorubicin, SAHA, arsenic trioxide, and etoposide.

First claim

We claim:

1. A method of treating multiple myeloma or lung cancer in a subject, comprising administering an effective amount of a cyclic compound and at least one other anti-cancer agent to the subject, wherein the cyclic compound comprises a recognition sequence and a non-recognition sequence, wherein said recognition sequence is joined to said non-recognition sequence by a first linker and a second linker, wherein said non-recognition sequence is five amino acids selected from KLKLK (SEQ ID NO:27), KLQLK (SEQ ID NO:28), QLKLK (SEQ ID NO:29), KLKLQ (SEQ ID NO:281), KQKLK (SEQ ID NO:30), KLKQK (SEQ ID NO:282), KXKXK (SEQ ID NO:31), or ELKLK (SEQ ID NO:32), where X=sarcosine and said recognition sequence is five amino acids selected from MVVSW (SEQ ID NO:33), MVVSA (SEQ ID NO:34), MVVAW (SEQ ID NO:35), MVASW (SEQ ID NO:36), MAVSW (SEQ ID NO:37), AVVSW (SEQ ID NO:38), N*VVSW (SEQ ID NO:39), N*VVYW (SEQ ID NO:40), N*VVAW (SEQ ID NO:41), AVVAW (SEQ ID NO:42), N*AVAW (SEQ ID NO:43), N*VAAW (SEQ ID NO:44), N*VLAW (SEQ ID NO:45), N*VIAW (SEQ ID NO:46), N*VFAW (SEQ ID NO:47), or WSVVW (SEQ ID NO:48), where N*=norleucine, and where said first linker and said second linker are independently selected from the structures:

wherein no more than one of said first linker and said second linker is D-Pro-L-Pro.

2. The method of claim 1 , wherein the at least one other anti-cancer agent comprises a cytotoxic agent, chemotherapeutic agent, or anti-signaling agent.

3. The method of claim 1 , wherein the at least one other anti-cancer agent comprises bortezomib, or a pharmaceutically acceptable salt thereof.

4. The method of claim 1 , wherein the cyclic compound has one of the following structures:

or a pharmaceutically acceptable salt of any of the foregoing.

5. The method of claim 3 , wherein the cyclic compound has one of the following structures:

or a pharmaceutically acceptable salt of any of the foregoing.

6. The method of claim 1 , wherein the cyclic compound has the structure:

or a pharmaceutically acceptable salt thereof.

7. The method of claim 3 , wherein the cyclic compound has the structure:

or a pharmaceutically acceptable salt thereof.

8. The method of claim 1 , wherein the subject has multiple myeloma.

9. The method of claim 1 , wherein the subject has lung cancer.

10. The method of claim 1 , wherein the subject is human.

11. The method of claim 1 , wherein the cyclic compound and the at least one other anti-cancer agent are administered concurrently.

12. The method of claim 1 , wherein the cyclic compound and the at least one other anti-cancer agent are administered consecutively.

13. The method of claim 1 , wherein the cyclic compound has the structure:

or a pharmaceutically acceptable salt thereof.

14. The method of claim 1 , wherein the at least one other anti-cancer agent comprises a proteasome inhibitor.

15. The method of claim 1 , wherein the subject is a mammal.

16. The method of claim 1 , wherein the subject is a non-human mammal.

Assignees

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

Inventors

• Hazlehurst Lori
• Mclaughlin Mark
• Jain Priyesh
• Dalton William S

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K38/00

  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) · CPC title

• A61K38/08

  Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)} · CPC title

• C07K7/06 Primary

  having 5 to 11 amino acids · CPC title