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 composition of matter comprising:
 (a) 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; or   (b) a composition comprising the cyclic compound of (a) and a pharmaceutically acceptable carrier; or   (c) a composition comprising a HYD1 peptide and at least one other anti-cancer agent.   
     
     
         2 . The composition of matter of  claim 1 , wherein the composition of matter comprises (a) and the cyclic compound has 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 composition of matter of  claim 2 , wherein the cyclic compound has the following structure: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The composition of matter of  claim 1 , wherein the composition of matter comprises (a), and wherein the cyclic compound comprises a cyclized peptide listed in Table 4, Table 5, or Table 8. 
     
     
         5 . The composition of matter of  claim 1 , wherein the composition of matter comprises (b), and wherein the composition further comprises at least one other anti-cancer agent. 
     
     
         6 . A method of using a cyclic compound, comprising:
 (a) treating a proliferation disorder, comprising administering an effective amount of the cyclic compound to a subject in need thereof; or   (b) suppressing the growth of malignant cells, comprising contacting the cells in vitro or in vivo with an effective amount of the cyclic compound,   wherein the cyclic compound comprises a recognition sequence and a non-recognition sequence, wherein the recognition sequence comprises at least four amino acids, wherein the non-recognition sequence comprises at least four amino acids, and wherein the recognition sequence is joined to the non-recognition sequence by a first linker and a second linker.   
     
     
         7 . The method of  claim 6 , further comprising administering at least one other anti-cancer agent to the subject of (a); or contacting at least one other anti-cancer agent to the malignant cells of (b). 
     
     
         8 . The method of  claim 7 , 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. 
     
     
         9 . The method of  claim 6 , wherein the method comprises (a), and wherein the proliferation disorder comprises multiple myeloma or other hematologic malignancy. 
     
     
         10 . The method of  claim 6 , wherein the method comprises (b), and wherein the malignant cells comprise multiple myeloma cells or cells of another hematologic malignancy. 
     
     
         11 . The method of  claim 6 , wherein the method comprises (a), and wherein the proliferation disorder is a relapsing proliferation disorder. 
     
     
         12 . The method of  claim 6 , wherein the method comprises (b), and wherein the malignant cells are cells of a relapsing malignancy. 
     
     
         13 . A method for using a HYD1 peptide, comprising:
 (a) treating a malignancy in a subject, comprising administering a HYD1 peptide and at least one other anti-cancer agent to the subject in need thereof; or   (b) 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.   
     
     
         14 . The method of  claim 13 , 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, to the subject. 
     
     
         15 . The method of  claim 13 , wherein the HYD1 peptide comprises the all D-amino acid peptide KIKMVISWKG (HYD1) (SEQ ID NO:278). 
     
     
         16 . The method of  claim 13 , wherein the malignancy is multiple myeloma or another hematologic malignancy. 
     
     
         17 . A method for treating a malignancy in a subject, comprising administering an effective amount of a cyclic compound to the subject, wherein the cyclic compound has 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.