Compounds and pharmaceutical use thereof in the treatment of cancer

Abstract

The present invention relates to a compound or a pharmaceutical salt thereof comprising a hexapeptide sequence of formula (I), its method of synthesis and its use in anticancer therapy. The invention also relates to a pharmaceutical composition for use in the treatment of cancer comprising at least one soluble peptide according to the invention or at least one acid nucleic according to the invention or at least one expression vector according to the invention, or at least one host cell according to the invention and a pharmaceutically acceptable carrier.

1 - 19 . (canceled) 
     
     
         20 . A method of treating a disease treatable by inhibiting CD47 function in a subject in need thereof comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof comprising a hexapeptide sequence of formula (I):
   —X 1 —X 2 —X 3 —X 4 —X 5 —X 6 —   (I)
   
       wherein:
 X 1 , X 2 , X 3 , X 4 , X 5 , X 6  are independently linked to each other according to formula (I) via peptide bonds or at least one pseudopeptide bond; 
 X 1  is a residue chosen from the list consisting of substituted or unsubstituted phenylalanine, substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, and substituted or unsubstituted homo-phenylalanine; 
 X 2  is a residue chosen from the list consisting of substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, substituted or unsubstituted phenylalanine, homo-phenylalanine, homo-meta-tyrosine, homo-para-tyrosine and homo-ortho-tyrosine; 
 X 3  is a residue chosen from the list consisting of substituted or unsubstituted valine, substituted or unsubstituted alanine, substituted or unsubstituted leucine, and substituted or unsubstituted isoleucine; 
 X 4  is a residue chosen from the list consisting of substituted or unsubstituted valine, substituted or unsubstituted alanine, substituted or unsubstituted leucine, substituted and unsubstituted isoleucine; 
 X 5  is a residue chosen from the list consisting of substituted or unsubstituted methionine, methylated homo-cysteine, lysine, norleucine, leucine and isoleucine; 
 X 6  is a residue chosen from the list consisting of substituted or unsubstituted tryptophan, substituted or unsubstituted hetero-tryptophan, substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine, substituted or unsubstituted phenylalanine, and substituted or unsubstituted naphthyl-alanine; 
 X 1  is the N-terminal side of the molecule of formula (I), X 6  is the C-terminal side of the molecule of formula (I); 
 the hexapeptide sequence of formula (I) comprises at least one substituted or unsubstituted para-tyrosine, substituted or unsubstituted ortho-tyrosine, substituted or unsubstituted meta-tyrosine residue, 
 wherein said compound is an agonist of CD47, 
 with the proviso that none of the following peptides are covered: 
 
       
         
           
                 
               
                   KRFYGGMWKK 
                 
                     
                 
                   (D)KRFYGGMW(D)K 
                 
                     
                 
                   KRFYVVMWKK 
                 
                     
                 
                     (     )R -F-Y-V-V-M-W-K 
                 
                     
                 
                   R- (     )F -Y-V-V-M-W-K 
                 
                     
                 
                   R-F- (     )Y -V-V-M-W-K 
                 
                     
                 
                   R-F-Y- (     )V -V-M-W-K 
                 
                     
                 
                   R-F-Y-V- (     )V -M-W-K 
                 
                     
                 
                   R-F-Y-V-V- (     )M -W-K 
                 
                     
                 
                   R-F-Y-V-V-M- (     )W -K 
                 
                     
                 
                   R-F-Y-V-V-M-W- (     )K   
                 
                     
                 
                     (     )R-(     )F-(     )Y-(     )V-(     )V-(     )M-(     )W-   
                 
                     
                 
                     (     )K   
                 
                     
                 
                     (     )K-(     )W-(     )M-(     )V-(     )V-(     )Y-(     )F-   
                 
                     
                 
                     (     )R   
                 
                     
                 
                     Azido(     )K-(     )W-(     )M-(     )V-(     )V-(     )Y-   
                 
                     
                 
                     (     )F-(     )R   
                 
                     
                 
                     (     )K -R-F-Y-V-V-M-W-K-K 
                 
                     
                 
                   K- (     )R -F-Y-V-V-M-W-K-K 
                 
                     
                 
                   K-R- (     )F -Y-V-V-M-W-K-K 
                 
                     
                 
                   K-R-F- (     )Y -V-V-M-W-K-K 
                 
                     
                 
                   K-R-F-Y- (     )V -V-M-W-K-K 
                 
                     
                 
                   K-R-F-Y-V- (     )V -M-W-K-K 
                 
                     
                 
                   K-R-F-Y-V-V- (     )M -W-K-K 
                 
                     
                 
                   K-R-F-Y-V-V-M- (     )W -K-K 
                 
                     
                 
                   R-R-F-V-V-V-M-W- (     )K -K 
                 
                     
                 
                   R-R-F-V-V-V-M-W-K- (     )K   
                 
                     
                 
                   K-R-F-Y-V-V-M-W-K- (     )R   
                 
                     
                 
                     (     )K -R-F-Y-V-V-M-W-K- (     )K   
                 
                     
                 
                     (     )K-(     )R-(     )F-(     )Y-(     )V-(     )V-(     )M-   
                 
                     
                 
                     (     )W-(     )K-(     )K   
                 
                     
                 
                     (     )K-(     )K-(     )W-(     )M-(     )V-(     )V-(     )Y-   
                 
                     
                 
                     (     )F-(     )R-(     )K   
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 7  refers to methionine, methionine sulfoxide, methionine sulfone or alanine or butylglycine or lysine side chains, 
       
       
         
           
           
               
               
           
         
         wherein R 4  refers to methionine or alanine or butylglycine or lysine side chains; 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         21 . The method according to  claim 20 , wherein the compound or the pharmaceutically acceptable salt is in linear form or in cyclic form. 
     
     
         22 . The method according to  claim 20 , wherein the disease is cancer. 
     
     
         23 . The method according to  claim 20 , wherein the disease is adrenal cortical cancer, anal cancer, bile duct cancer, bladder cancer, bone cancer, brain and central nervous system cancer, breast cancer, Castleman disease, cervical cancer, colorectal cancer, endometrial cancer, esophagus cancer, gallbladder cancer, gastrointestinal carcinoid tumors, Hodgkin's disease, non-Hodgkin's lymphoma, Kaposi's sarcoma, kidney cancer, laryngeal and hypopharyngeal cancer, liver cancer, lung cancer, mesothelioma, plasmacytoma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cavity and oropharyngeal cancer, ovarian cancer, pancreatic cancer, penile cancer, pituitary cancer, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, thymus cancer, thyroid cancer, vaginal cancer, vulvar cancer, and uterine cancer, or in the prevention and the treatment of leukemia and particularly in acute lymphoblastic leukemia, B-chronic lymphocytic leukemia, hairy-cell leukemia, adult T-cell leukemia, prolymophocytic leukaemia of T-cell type or myeloid leukaemia. 
     
     
         24 . The method according to  claim 20 , wherein the compound or the pharmaceutically acceptable salt thereof of formula (III):
 acceptable salt thereof of formula (III):
   -A-B—Xi-X2-X3-X4-X5-X6-C-D-   (III),
 
   wherein   A is a (D)-Lysine, B is a (L)-Arginine, C is a (L)-Lysine, D is a (D)-Lysine;   A and B are linked to each other by a pseudopeptide bond —CO-NMe-; and   X1-X2-X3-X4-X5-X6 is FYVVMW, FYVVXW (SEQ ID NO: 1), FYVVIW (SEQ ID NO: 2), FYVVKW (SEQ ID NO: 3) or FYVVLW (SEQ ID NO: 4), wherein X is norleucine.   
     
     
         25 . The method according to  claim 20 , wherein the compound is H-(D)K p (CONMe) R F Y V V M W K (D)K—OH (SEQ ID NO: 18). 
     
     
         26 . The method according to  claim 20 , wherein the compound is H-(D)K p (CONMe) R F Y V V X W K (D)K—OH (SEQ ID NO: 21). 
     
     
         27 . The method according to  claim 20 , wherein the compound is H-(D)K p (CONMe) R F Y V V L W K (D)K—OH (SEQ ID NO: 22). 
     
     
         28 . The method according to  claim 20 , wherein the compound is H-(D)K p (CONMe) R F Y V V I W K (D)K—OH (SEQ ID NO: 23). 
     
     
         29 . The method according to  claim 20 , wherein the method further comprises the administration of a further therapeutic active agent. 
     
     
         30 . The method according to  claim 20 , wherein the method further comprises the administration of an anticancer agent selected from the group of: fludarabine, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, platinum complexes, carboplatin and oxaliplatin, mitomycin, dacarbazine, procarbazine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epimbicm, 5-fluorouracil, taxanes such as docetaxel and paclitaxel, leucovorin, levamisole, irinotecan, estramustine, etoposide, nitrogen mustards, BCNU, nitrosoureas such as carmustme and lomustine, vinca alkaloids such as vinblastine, vincristine and vinorelbine, imatimb mesylate, hexamethyhnelamine, topotecan, kinase inhibitors, phosphatase inhibitors, ATPase inhibitors, tyrphostins, protease inhibitors, inhibitors herbimycm A, genistein, erbstatin, and lavendustin A. 
     
     
         31 . The method according to  claim 20 , wherein the method further comprises the administration of an anticancer agent selected from the group of alkylating agents, plant alkaloids, DNA topoisomerase inhibitors, anti-folates, pyrimidine analogs, purine analogs, DNA antimetabolites, taxanes, podophyllotoxin, hormonal therapies, retinoids, photo sensitizers or photodynamic therapies, angiogenesis inhibitors, antimitotic agents, isoprenylation inhibitors, cell cycle inhibitors, actinomycins, bleomycins, anthracyclines, MDR inhibitors and Ca 2+  ATPase inhibitors. 
     
     
         32 . The method according to  claim 20 , wherein the method further comprises the administration of an anticancer agent selected from the group of cytokines, chemokines, growth factors, growth inhibitory factors, hormones, soluble receptors, decoy receptors, monoclonal or polyclonal antibodies, mono-specific, bi-specific or multi-specific antibodies, monobodies, polybodies. 
     
     
         33 . The method according to  claim 20 , wherein the method further comprises the administration of an anticancer agent selected from the group of growth or hematopoietic factors such as erythropoietin and thrombopoietin, and growth factor mimetics thereof. 
     
     
         34 . The method according to  claim 20 , wherein the method further comprises the administration of an antiemetic agent selected from the group of metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoemanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dunenhydrinate, diphenidol, dolasetron, meclizme, methallatal, metopimazine, nabilone, oxypemdyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine, thioproperazine and tropisetron. 
     
     
         35 . The method according to  claim 20 , wherein the method further comprises the administration of a hematopoietic colony stimulating factor selected from the group of filgrastim, sargramostim, molgramostim and epoietin alpha. 
     
     
         36 . The method according to  claim 20 , wherein the method further comprises the administration of an opioid analgesic agent selected from the group of morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, nomioiphine, etoipbine, buprenorphine, mepeddine, lopermide, anileddine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazodne, pemazocine, cyclazocine, methadone, isomethadone and propoxyphene. 
     
     
         37 . The method according to  claim 20 , wherein the method further comprises the administration of a non-opioid analgesic agent selected from the group of aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac. 
     
     
         38 . The method according to  claim 20 , wherein the method further comprises the administration of an anxiolytic agent selected from the group of uspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.