Ship inhibition to induce expression of granulocyte colony stimulating factor in a subject

Abstract

The present invention relates to the use SHIP inhibitors to induce expression of granulocyte colony stimulating factor (G-CSF) in a subject, thereby promoting expansion of hematopoietic and mesenchymal stem cells. The present invention generally relates to new uses of SHIP inhibitors for therapeutic purposes. More particularly, the present invention relates to the use of SHIP inhibitors, including, without limitation, SHIP and/or pan-SHIP1/2 inhibitors, for the inhibition of SHIP to induce expression of granulocyte colony stimulating factor (G-CSF) to treat various-diseases or conditions.

1 . A method of inducing expression of granulocyte colony stimulating factor (G-CSF) in a subject, said method comprising:
 administering a safe and effective amount of a SHIP1 inhibitor or a pan-SHIP1/2 inhibitor to the subject.   
     
     
         2 . The method according to  claim 1 , wherein the SHIP I inhibitor is a SHIP inhibitor compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein formula (I) is as follows: 
       
         
           
           
               
               
           
         
       
       wherein
    at the 4,5 and 5,6 positions represents a single or double bond, with the proviso that the sum of double bonds present at the 4,5 and 5,6 positions is 0 or 1. 
 R 1  is a straight chain C1-C4 alkyl or C1-C4 haloalkyl; 
 R 2  is hydrogen, methyl, or halomethyl; 
 R 3  and R 13  (when present), are individually selected from hydrogen, substituted or unsubstituted amino, C1-C4 alkyl, C1-C4 haloalkyl, and C1-C4 alkenyl; 
 R 4  is hydrogen, hydroxy, substituted or unsubstituted amino, C1-C4 alkyl, or benzyl; 
 R 5  represents hydrogen or an alkyl group; 
 X 1  is selected from the group consisting of hydrogen, hydroxy, mercapto, alkoxy, aryloxy, alkylthio, arylthio, alkylcarbonamido, alkoxycarbonamido, arylcarbonamido, aryloxycarbonamido, alkylsulfonamido, arylsulfonamido, substituted or unsubstituted amino, and aminoalkyl; and 
 each X 2  individually represents a divalent oxo atom or two hydrogen atoms; 
 with the proviso that X 1  cannot be a primary amino group when: R 1  and R 2  are each methyl; X 2 , R 3 , R 4 , and R 13  are each hydrogen; and R 5  represents a 1, 5-dimethylhexyl alkyl group. 
 
     
     
         3 . The method according to  claim 2 , wherein at least one of X 1 , R 3 , and R 4  is substituted or unsubstituted amino. 
     
     
         4 . The method according to  claim 3 , wherein the substituted or unsubstituted amino is NH 2  or NH 3 Cl. 
     
     
         5 . The method according to  claim 2 , wherein X 1  is NH 2  or NH 3 Cl. 
     
     
         6 . The method according to  claim 2 , wherein said compound of formula (I) is a compound of a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof,
 wherein X=NR 2 , NRCOR, NHCONR 2 , OR, SR, OCOR, OCONR 2 , or NHCNHNH 2 , and wherein R=H, alkyl, cycloalkyl, aryl, or benzyl. 
 
     
     
         7 . The method according to  claim 1 , wherein the pan-SHIP1/2 inhibitor is a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method according to  claim 6 , wherein the compound of Formula (I) or pharmaceutically acceptable salt thereof is a compound of Formula (IA) or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
       wherein
    represents a single or double bond; 
 R 1  and R 2  are individually selected from hydrogen and C 1-3  alkyl; 
 R 3  selected from hydrogen and amino; 
 R 4  is selected from hydrogen, amino, and hydroxy; 
 R 5  is selected from hydrogen and C 1-10  alkyl; and 
 X 1  is selected from hydrogen, amino, and hydroxy. 
 
     
     
         9 . The method according to  claim 8 , comprising administering a hydrochloride salt of a compound of Formula (IA). 
     
     
         10 . The method according to  claim 8 , comprising administering a compound of one of the following Formulas (IB)-(IO), or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The method according to  claim 1 , wherein the SHIP1 inhibitor or the pan-SHIP1/2 inhibitor is a compound having a formula selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method according to  claim 1 , wherein the SHIP1 or pan-SHIP1/2 inhibitor is administered orally, rectally, intraperitoneally, transdermally, intradermally, topically, by inhalation, nasally, buccally, vaginally, via an implanted reservoir or by parenteral routes. 
     
     
         13 . The method according to  claim 12 , wherein the SHIP1 or pan-SHIP1/2 inhibitor is injected intraperitoneally at between about 10 mg/kg and 80 mg/kg of body weight. 
     
     
         14 . The method according to  claim 1 , wherein administering a safe and effective amount of a SHIP1 inhibitor or a pan-SHIP1/2 inhibitor results in an increase in number of hematopoietic stem cells and/or mesenchymal stem cells in the subject. 
     
     
         15 . The method according to  claim 1 , wherein administering a safe and effective amount of a SHIP1 inhibitor or a pan-SHIP1/2 inhibitor results in an increase in number of neutrophils in the patient. 
     
     
         16 . The method according to  claim 1 , wherein the subject is suffering from a bacterial, fungal, or parasitic infection, a cancer, chemotherapy- or radiation-induced neutropenia, radiation-induced myeloablation, the effects of immunosuppressive drugs, or declining stem cell function associated with genetic, environmental or age-related factors. 
     
     
         17 . The method according to  claim 1 , wherein the SHIP1 inhibitor is either a small interfering RNA (siRNA) or a microRNA (miRNA) effective to inhibit SHIP1 via RNA interference (RNAi) (post transcriptional gene silencing). 
     
     
         18 . The method according to  claim 1 , wherein the SHIP1 inhibitor or the pan-SHIP1/2 inhibitor is