Senolytic Compositions and Uses Thereof

Abstract

Provided herein are senolytic agents for selectively killing senescent cells that are associated with numerous pathologies and diseases, including age-related pathologies and diseases. As disclosed herein, senescent cell-associated diseases and disorders may be treated or prevented by administering at least one senolytic agent or pharmaceutical compositions thereof. The senescent cell-associated diseases or disorders treated or prevented by the methods described herein include, but are not limited to, cardiovascular diseases or disorders, cardiovascular diseases and disorders associated with arteriosclerosis, such as atherosclerosis, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), osteoarthritis, inflammatory diseases or disorders, autoimmune diseases or disorders, pulmonary diseases or disorders, neurological diseases or disorders, dermatological diseases or disorders, chemotherapeutic side effects, radiotherapy side effects, metastasis and metabolic diseases.

What is claimed is: 
     
         1 . A compound of formula (IV) or (V) or pharmaceutically acceptable salts, hydrates or solvates thereof: 
       
         
           
           
               
               
           
         
       
       wherein R is a residue of a hydroxamic acid derivative histone deacetylase inhibitor, each of R 13 , R 14 , R 15 , R 16 , R 23 , R 24  and R 25  is independently hydrogen, C(O)—R 1 , a moiety of formula (VI) or a moiety of formula (VII): 
       
         
           
           
               
               
           
         
       
       each R 33 , R 34 , R 35 , R 36 , R 43 , R 4  and R 45  are independently hydrogen or —C(O)—R 2 ; each R 1  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 13 , R 14 , R 15  or R 16  is a moiety of formula (VI) or formula (VII) then the remainder of R 13 , R 14 , R 15  and R 16  is hydrogen or C(O)—R 1 ; and each R 2  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 23 , R 24  or R 25  is a moiety of formula (VI) or formula (VII) then the remainder of R 23 , R 24  or R 25  is hydrogen or —C(O)—R 1 ; provided that when each of R 13 , R 14 , R 15  and R 16  is hydrogen then R is not 7-heptanoyl phenylamide. 
     
     
         2 . The compound of  claim 1 , wherein the anomeric carbon of the pyranose ring (labelled *) is of the S configuration and the compounds are respectively β-D-galactoside and α-L-fucoside conjugates of hydroxamic acid derivative histone deacetylase inhibitors. 
     
     
         3 . The compound of  claim 2 , wherein the hydroxamic acid derivative histone deacetylase inhibitor is selected from the group consisting of panobinostat, quisinostat, vorinostat, dacinostat, givinostat, CUDC-907, CUDC-101, abexinostat, belinostat pracinostat, resminostat, ricolinostat, pyroxamide, APHA, trichostatin A, oxamflatin and AR-42. 
     
     
         4 . The compound of  claim 3  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 3  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . The compound of  claim 3  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . A compound of formulae (XI), (XII), (XIII) or (XIV) or pharmaceutically acceptable salts, hydrates or solvates thereof: 
       
         
           
           
               
               
           
         
       
       wherein Y is carbonyl or is absent; A is a substituted or benzofused 5-membered heteroaryl or heterocyclic group containing at least one nitrogen atom; B is selected from the group consisting of ethyl, isopropyl or chloro; each of R 13 , R 14 , R 15 , R 16 , R 23 , R 24  and R 25  is independently hydrogen, C(O)—R 1 , a moiety of formula (VI) or a moiety of formula (VII): 
       
         
           
           
               
               
           
         
       
       each R 33 , R 34 , R 35 , R 36 , R 43 , R 44  and R 45  are independently hydrogen or —C(O)—R 2 ; each R 1  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 13 , R 14 , R 15  or R 16  is a moiety of formula (VI) or formula (VII) then the remainder of R 13 , R 14 , R 15  and R 16  is hydrogen or C(O)—R 1 ; and each R 2  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 23 , R 24  or R 25  is a moiety of formula (VI) or formula (VII) then the remainder of R 23 , R 24  or R 25  is hydrogen or —C(O)—R 1 . 
     
     
         8 . The compound of  claim 7 , wherein the anomeric carbon of the pyranose ring (labelled *) is of the S configuration and the compounds are respectively β-D-galactoside and α-L-fucoside conjugates of Hsp90 inhibitors. 
     
     
         9 . The compound of  claim 8 , wherein the moiety A-Y—C 6 H 2 (OH) 2 —B is an Hsp90 inhibitor selected from the group consisting of luminespib (NVP-AUY922), ganetespib, VER-50589, AT13387 and KW-2478. 
     
     
         10 . The compound of  claim 9  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A compound of formulae (XVI), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV) or (XXV) or pharmaceutically acceptable salts, hydrates or solvates thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein R 8  is 4-morpholinyl or 1-imidazolyl; each R 13 , R 14 , R 15 , R 16 , R 23 , R 24  and R 25  are independently hydrogen, C(O)—R 1 , a moiety of formula (VI) or a moiety of formula (VII): 
       
         
           
           
               
               
           
         
       
       each R 33 , R 34 , R 35 , R 36 , R 43 , R 44  and R 45  are independently hydrogen or —C(O)—R 2 ; each R 1  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 13 , R 14 , R 15  or R 16  is a moiety of formula (VI) or formula (VII) then the remainder of R 13 , R 14 , R 15  and R 16  are hydrogen or C(O)—R 1 ; and each R 2  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 23 , R 24  or R 25  is a moiety of formula (VI) or formula (VII) then the remainder of R 23 , R 24  or R 25  is hydrogen or —C(O)—R 1 . 
     
     
         12 . The compound of  claim 11 , wherein the anomeric carbon of the pyranose ring (labelled *) is of the S configuration and the compounds are respectively β-D-galactoside and α-L-fucoside conjugates of TOP1 inhibitors. 
     
     
         13 . The compound of  claim 12  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 12  having any of the structures: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . A compound of formulae (XXVIII) or (XXIX) or pharmaceutically acceptable salts, hydrates or solvates thereof: 
       
         
           
           
               
               
           
         
       
       wherein R 9  is hydrogen, C 1-4  alkyl, CF 3 , CN or NO 2 ; R 10  is hydrogen, C 1-4  alkyl or arylalkyl; each of R 13 , R 14 , R 15 , R 16 , R 23 , R 24  and R 25  are independently hydrogen, C(O)—R 1 , a moiety of formula (VI) or a moiety of formula (VII): 
       
         
           
           
               
               
           
         
       
       each R 33 , R 34 , R 35 , R 36 , R 43 , R 44  and R 45  are independently hydrogen or C(O)—R 2 , each R 1  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 13 , R 14 , R 15 , or R 16  is a moiety of formula (VI) or formula (VII) then the remainder of R 13 , R 14 , R 15  and R 16  is hydrogen or C(O)—R 1 ; and each R 2  is independently C 1-4  alkyl or phenyl, with the proviso that if one of R 23 , R 24  or R 25  is a moiety of formula (VI) or formula (VII) then the remainder of R 23 , R 24  or R 25  is hydrogen or C(O)—R 1 ; provided that in a compound of formula (XXVIII) when R 9  is NO 2  and R 10  is benzyl, then each of R 13 , R 14 , R 15 , R 16  are not simultaneously hydrogen or acetyl. 
     
     
         16 . A method for treating a senescence-associated disease or disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a compound of  claim 1  or pharmaceutical compositions thereof. 
     
     
         17 . A method for treating a senescence-associated disease or disorder comprising administering to a subject in need thereof a therapeutically-effective amount of a compound or pharmaceutically acceptable salts, pharmaceutical compositions, hydrates or solvates thereof, of formula: 
       
         
           
           
               
               
           
         
       
       wherein R 46  is either hydrogen, acetyl or propionyl. 
     
     
         18 . The method of  claim 16  wherein the senescence-associated disease or disorder is an age-related disorder selected from the group consisting of renal disease, renal failure, frailty, cognitive impairment, hearing loss, muscle fatigue, skin conditions, skin wound healing, liver fibrosis, pancreatic fibrosis, oral submucosa fibrosis, and sarcopenia. 
     
     
         19 . The method of  claim 16 , wherein the senescence-associated disease or disorder is a pulmonary disease selected from the group consisting of pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, cystic fibrosis, emphysema, bronchiectasis, and age-related loss of pulmonary function. 
     
     
         20 . The method of  claim 16 , wherein the senescence-associated disease or disorder is metastasis, a chemotherapeutic side effect or a radiotherapy side effect.