Killing senescent cells and treating senescence-associated conditions using a src inhibitor and a flavonoid

Abstract

Provided herein are methods and uses for treatment or prophylaxis of a senescent cell associated disease or disorder by administering a senolytic combination comprising dasatinib and quercetin or an analog thereof to a subject in need thereof. In certain embodiments, the senescent cell associated disease or disorder is a cardiovascular disease or disorder, inflammatory disease or disorder, a pulmonary disease or disorder, a neurological disease or disorder, or a metabolic disease or disorder.

1 . A method for treating a senescence associated disease or disorder in a subject comprising administering to the subject a senolytic combination,
 wherein the senescence associated disease or disorder is not cancer; and   wherein the senolytic combination includes a src inhibitor and a flavonoid.   
     
     
         2 . The method of  claim 1 , wherein the senolytic combination is administered once every 0.5-12 months; provided that if the senescence associated disease or disorder is a senescence associated metabolic disorder, the senolytic combination is administered once every 4-12 months. 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein the senescence associated disease or disorder is atherosclerosis. 
     
     
         5 . The method of  claim 1 , wherein the senescence associated disease or disorder is osteoarthritis. 
     
     
         6 . The method of  claim 1 , wherein the senescence associated disease or disorder is idiopathic pulmonary fibrosis or chronic obstructive pulmonary disease. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 1 , wherein the senescence associated disease or disorder is selected from diabetes, metabolic syndrome, and obesity. 
     
     
         9 .- 10 . (canceled) 
     
     
         11 . A method of killing a senescent cell, comprising contacting the senescent cell with a src inhibitor and a flavonoid. 
     
     
         12 . The method of  claim 11 , wherein the senescent cell is selected from a senescent fibroblast, a senescent pre-adipocyte, a senescent epithelial cell, a senescent chondrocyte, a senescent neuron, and a senescent endothelial cell. 
     
     
         13 . The method of  claim 11 , wherein the senescent cell is a senescent pre-adipocyte. 
     
     
         14 . The method of  claim 11 , wherein the src inhibitor is dasatinib. 
     
     
         15 . The method of  claim 11 , wherein the flavonoid is a compound having a structure of the following formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 1  is —OH or —H; 
 R 2  is —OH or —H; 
 R 3  is —OH, —H, —R 6 , or —OCH 2 PO(OH) 2 ; 
 R 4  is —OH, —OPO(OH) 2 , —OCH 3 , —OCH 2 PO(OH) 2 , —R 6 , —H, or —OSO 3 H; and 
 R 5  is —OH, —H, —R 6 , or —OCH 3 , 
 wherein R 6  is 
 
       
       
         
           
           
               
               
           
         
       
     
     
         16 . (canceled) 
     
     
         17 . The method of  claim 15  wherein R 3  is —OH. 
     
     
         18 .- 19 . (canceled) 
     
     
         20 . The method of  claim 15  wherein R 4  is —OH or —OSO 3 H. 
     
     
         21 . The method of  claim 15  wherein R 5  is —OH. 
     
     
         22 . The method of  claim 15  wherein the compound of Formula (I) is selected from the following structures and pharmaceutically acceptable salts thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . The method of  claim 1 , wherein the senolytic combination is administered during a treatment course of 1-7 days once every 0.5-12 months. 
     
     
         24 . The method of  claim 1 , wherein the senescence associated disease or disorder is a senescence associated metabolic disorder, and the senolytic combination is administered during a treatment course of 1-7 days once every 4-12 months. 
     
     
         25 . The method of  claim 1 , wherein the src inhibitor is dasatinib. 
     
     
         26 . The method of  claim 1 , wherein the flavonoid is a compound having a structure of the following formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 1  is —OH or —H; 
 R 2  is —OH or —H; 
 R 3  is —OH, —H, —R 6 , or —OCH 2 PO(OH) 2 ; 
 R 4  is —OH, —OPO(OH) 2 , —OCH 3 , —OCH 2 PO(OH) 2 , —R 6 , —H, or —OSO 3 H; and 
 R 5  is —OH, —H, —R 6 , or —OCH 3 ; 
 
       
       wherein R 6  is 
       
         
           
           
               
               
           
         
       
     
     
         27 . The method of  claim 26 , wherein the compound of Formula (I) is selected from the following structures and pharmaceutically acceptable salts thereof: