Panicein compounds, compositions and uses thereof

Abstract

The present invention relates to the fields of medicine and cancer treatment. The invention more specifically relates to the use of a panicein or a derivative thereof, to decrease or inhibit, in vitro or ex vivo, the Patched receptor drug efflux activity, in particular the chemotherapeutic drug efflux activity and chemotherapy resistance. The present disclosure further relates to uses of such compounds, in particular to prepare a pharmaceutical composition to allow or improve the efficiency of a therapy of cancer in a subject in need thereof. The compound of the invention can indeed be advantageously used, in combination with at least one chemotherapeutic drug, for treating cancer, for preventing cancer metastasis and/or for preventing cancer recurrence in a subject. The invention also discloses methods for preventing or treating cancer, cancer metastasis and/or cancer recurrence in a subject, as well as kits suitable for preparing a composition according to the present invention and/or for implementing the herein described methods.

1 - 16 . (canceled) 
     
     
         17 . A method for decreasing or inhibiting, in vitro or ex vivo, the Patched receptor drug efflux activity comprising a step of contacting a cancer cell with a panicein compound, or of a derivative or analogue thereof. 
     
     
         18 . The method according to  claim 17 , wherein the panicein compound is a compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, C 1 -C 6  alkyl, C 1 -C 6  aminoalkyl, C 1 -C 6  hydroxyalkyl, C 1 -C 6  halogenoalkyl or —OR 4 , 
 R 2  is H or C 1 -C 6  alkyl, 
 R 3  is C 1 -C 6  alkyl, —CH 2 OR 4 , —C(═O)R 4 , —C(═O)OR 4 , —C(═O)NHR 4 , or —CH 2 NHR 4 , 
 each R 4  is independently —H, or C 1 -C 6  alkyl, 
 R is selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
             wherein:
 bonds (1) and (2) are independently of each other a single bound or a double bond, 
 R 5  is present when bond (1) is a single bond, and represents —H, or —OR 6 , and 
 when present, each R 6  is independently H or a C 1 -C 6  alkyl; 
 
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         19 . The method according to  claim 18 , wherein the compound of formula (I) is such that R is selected in the group consisting of: 
       
         
           
           
               
               
           
         
       
       when present. 
     
     
         20 . The method according to  claim 18 , wherein the compound of formula (I) comprises one or several of the following features:
 i) R 1  is H, C 1 -C 6  alkyl, or —OR 4 , and/or   ii) R 2  is H or C 1 -C 6  alkyl, and/or   iii) R 3  is C 1 -C 6  alkyl, —CH 2 OR 4  or, —C(═O)R 4 , and/or   iv) each R 4  is independently —H, or a C 1 -C 6  alkyl or a C 1 -C 3  alkyl.   
     
     
         21 . The method according to  claim 18 , wherein the compound of formula (I) is selected from Panicein C, Panicein B3, Panicein B2 and Panicein A hydroquinone. 
     
     
         22 . The method according to  claim 21 , wherein the compound of formula (I) is selected from Panicein A hydroquinone and a stereoisomer, derivative or analog thereof. 
     
     
         23 . The method according to  claim 17 , wherein the drug is a chemotherapeutic drug. 
     
     
         24 . The method according to  claim 18 , wherein bonds (1) and (2) are not simultaneously double bonds. 
     
     
         25 . The method according to  claim 19 , wherein R 6  is H and R 5  is H or OH. 
     
     
         26 . A method for treating cancer, for reducing cancer metastasis and/or cancer recurrence in a subject comprising a step of administering a panicein compound in combination with at least one chemotherapeutic drug in the subject. 
     
     
         27 . The method according to  claim 26 , wherein the cancer cell expresses the Patched receptor. 
     
     
         28 . The method according to  claim 27 , wherein cancer is selected from a melanoma, a breast cancer, a thyroid cancer, a prostate cancer, a colon cancer, a rectal cancer, an oesophagus cancer, a gastric cancer, an ovarian cancer, a lung cancer, a pancreatic cancer, a glioma, an adrenocortical carcinoma, a pediatric solid malignant tumor, a leukaemia, a multiple myeloma or a sarcoma. 
     
     
         29 . The method according to  claim 26 , wherein the at least one chemotherapeutic drug is selected from cisplatin, doxorubicin, methotrexate, temozolomide, 5-FU, dacarbazine and vemurafenib. 
     
     
         30 . The method according to  claim 26 , wherein the subject is a mammal. 
     
     
         31 . The method according to  claim 30 , wherein the subject is a human being suffering of a cancer and resistant to chemotherapy. 
     
     
         32 . A composition comprising at least one panicein compound and at least one chemotherapeutic drug. 
     
     
         33 . A method for treating cancer, for reducing cancer metastasis and/or cancer recurrence in a subject comprising a step of administering the composition according to  claim 32  in the subject. 
     
     
         34 . A kit comprising at least one panicein compound and at least one chemotherapeutic drug in distinct containers. 
     
     
         35 . A method for preparing a composition comprising at least one panicein compound and at least one chemotherapeutic drug comprising mixing a composition comprising at least one panicein compound and at least one chemotherapeutic drug.