KILLING SENESCENT CELLS AND TREATING SENESCENCE-ASSOCIATED CONDITIONS USING A SRC INHIBITOR AND A FLAVONOID
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: