Integrin interaction inhibitors for the treatment of cancer

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.

We claim: 
     
         1 . A cyclic compound comprising a recognition sequence and a non-recognition sequence, wherein said recognition sequence comprises at least four amino acids, wherein said non-recognition sequence comprises at least four amino acids, and wherein said recognition sequence is joined to said non-recognition sequence by a first linker and a second linker. 
     
     
         2 . The compound of  claim 1 , having the following structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is K; 
         wherein R 2  is L; 
         wherein R 3  is K; 
         wherein R 4  is L; 
         wherein R 5  is K; 
         wherein R 6  is selected from the group consisting of W, A, and M; 
         wherein R 7  is selected from the group consisting of S, A, Y, and V; 
         wherein R 8  is selected from the group consisting of V and A; 
         wherein R 9  is selected from the group consisting of V, A, and S; and 
         wherein R 10  is selected from the group consisting of M, A, W, and nor-Leu. 
       
     
     
         3 . The compound of  claim 2 , wherein the compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 1 , wherein said compound comprises a cyclized peptide listed in Table 4, Table 5, or Table 8. 
     
     
         5 . A composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier. 
     
     
         6 . The composition of  claim 5 , further comprising at least one other anti-cancer agent. 
     
     
         7 . The composition of  claim 6 , wherein said at least one anti-cancer agent is selected from among suberoylanilide hydroxamic acid (SAHA) or other histone deacetylase inhibitor, arsenic trioxide, doxorubicin or other anthracycline DNA intercalating agent, and etoposide or other topoisomerase II inhibitor. 
     
     
         8 . A method of treating a proliferation disorder, comprising administering an effective amount of a compound of  claim 1  to a subject in need thereof. 
     
     
         9 . The method of  claim 8 , further comprising administering at least one other anti-cancer agent to the subject. 
     
     
         10 . The method of  claim 9 , wherein the at least one anti-cancer agent is selected from among suberoylanilide hydroxamic acid (SAHA) or other histone deacetylase inhibitor, arsenic trioxide, doxorubicin or other anthracycline DNA intercalating agent, and etoposide or other topoisomerase II inhibitor. 
     
     
         11 . A method of suppressing the growth of malignant cells, comprising contacting the cells in vitro or in vivo with an effective amount of a HYD1 peptide, and at least one other anti-cancer agent. 
     
     
         12 . The method of  claim 11 , wherein the malignant cells are cells of a multiple myeloma or another hematologic malignancy. 
     
     
         13 . The method of  claim 11 , wherein the HYD1 peptide comprises the all D-amino acid peptide KIKMVISWKG (HYD1) (SEQ ID NO:278). 
     
     
         14 . The method of  claim 11 , wherein the malignancy expresses CD44.