Compositions and methods for selectively depleting senescent cells

1. A method of selectively killing one or more senescent cells from a cell population or tissue, the method comprising contacting the senescent cells with an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound comprising Formula (II):

wherein:

X is selected from the group consisting of C(O), C(S), C(NH) and S(O) 2 ;

Y is selected from the group consisting of O, NH and S;

n is 1;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR, SR, NRR, NRCOR, NRCONRR, NRCO 2 R, COR, CO 2 R, NOR, NO 2 , CONRR, OC(O)NRR, SO 2 R, SO 2 NRR, NRSO 2 R, NRSO 2 NRR, C(O)C(O)R, and C(O)CH 2 C(O)R, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

A is selected from the group consisting of

wherein:

R 9 and R 10 are independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO 2 R′, COR′, CO 2 R′, NOR′, NO 2 , CONR′R′, OC(O)NR′R′, SO 2 R, SO 2 NR′R′, NR′SO 2 R′, NR′SO 2 NR′R′, C(O)C(O)R′, and C(O)CH 2 C(O)R′, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R′ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R′ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

Optionally, R 9 and R 10 are taken together to form a 5-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

B is

wherein:

R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR″, SR″, NR″R″, NR″COR″, NR″CONR″R″, NRCO 2 R″, COR″, CO 2 R″, NOR″, NO 2 , CONR″R″, OC(O)NR″R″, SO 2 R″, SO 2 NR″R″, NR″SO 2 R″, NR″SO 2 NR″R″, C(O)C(O)R″, and C(O)CH 2 C(O)R″, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R″ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R″ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

Optionally, R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , and R 14 and R 15 are taken together to form a 4-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

m is an integer from 0-6; and

or B is one or more monocyclic aryl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

wherein any and all of the substituted described are substituted with one or more groups that are independently a methyl group or methoxy group.

2. The method of claim 1 , wherein the senescent cells are senescent due to replicative cellular senescence, premature cellular senescence, or therapy-induced senescence.

3. The method of claim 1 , wherein the senescent cells are from an age-related pathology.

4. The method of claim 1 , wherein the composition further comprises at least one inhibitor of one or more anti-apoptotic proteins in the Bcl-2 family.

5. The method of claim 4 , wherein the inhibitor is ABT263.

6. The method of claim 1 , wherein the cell population or tissue is in a human subject.

7. The method of claim 6 , wherein the subject has a received DNA-damaging therapy.

8. A method of killing therapy-induced senescent cells from a cell population or tissue, the method comprising contacting the therapy-induced senescent cells with an effective amount of a composition comprising a pharmaceutically acceptable carrier and a compound comprising formula (II):

wherein:

X is selected from the group consisting of C(O), C(S), C(NH) and S(O) 2 ;

Y is selected from the group consisting of O, NH and S;

n is 1;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR, SR, NRR, NRCOR, NRCONRR, NRCO 2 R, COR, CO 2 R, NOR, NO 2 , CONRR, OC(O)NRR, SO 2 R, SO 2 NRR, NRSO 2 R, NRSO 2 NRR, C(O)C(O)R, and C(O)CH 2 C(O)R, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

A is selected from the group consisting of

wherein:

R 9 and R 10 are independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR′, SR′, NR′R′, NR′COR′, NR′CONR′R′, NR′CO 2 R′, COR′, CO 2 R′, NOR′, NO 2 , CONR′R′, OC(O)NR′R′, SO 2 R, SO 2 NR′R′, NR′SO 2 R′, NR′SO 2 NR′R′, C(O)C(O)R′, and C(O)CH 2 C(O)R′, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R′ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R′ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

Optionally, R 9 and R 10 are taken together to form a 5-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

B is

wherein:

R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from the group consisting of hydrogen, deuterium, halogen, CF 3 , CN, OH, OCH 3 , OR″, SR″, NR″R″, NR″COR″, NR″CONR″R″, NRCO 2 R″, COR″, CO 2 R″, NOR″, NO 2 , CONR″R″, OC(O)NR″R″, SO 2 R″, SO 2 NR″R″, NR″SO 2 R″, NR″SO 2 NR″R″, C(O)C(O)R″, and C(O)CH 2 C(O)R″, a substituted or unsubstituted C1 to C6 alkyl, a substituted or unsubstituted C1 to C6 alkenyl, a substituted or unsubstituted C1 to C6 alkynyl, and a substituted or unsubstituted aryl;

R″ is independently selected from the group consisting of hydrogen, substituted C1-C4 aliphatic moiety, aliphatic moiety containing nitrogen, oxygen, or sulfur, or alternately, two R″ moieties bound to the same nitrogen atom are optionally taken together with the nitrogen atom to form a 3-7 membered saturated or unsaturated ring having 1-2 additional heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

Optionally, R 11 and R 12 , R 12 and R 13 , R 13 and R 14 , and R 14 and R 15 are taken together to form a 4-8 membered saturated or unsaturated ring having 0-3 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

m is an integer from 0-6; and

or B is one or more monocyclic aryl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, or sulfur;

wherein any and all of the substituted described are substituted with one or more groups that are independently a methyl group or methoxy group.

9. The method of claim 8 , wherein the composition further comprises at least one inhibitor of one or more anti-apoptotic proteins in the Bcl-2 family.

10. The method of claim 9 , wherein the inhibitor is ABT263.

11. The method of claim 8 , wherein the therapy-induced senescent cells are in a human subject.