Compositions and methods for selectively depleting senescent cells

Patent metadata

Field	Value
Publication number	US-10758524-B2
Application number	US-201816057021-A
Country	US
Kind code	B2
Filing date	Aug 7, 2018
Priority date	Jul 22, 2014
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises piperlongumine (PL) or derivative thereof. The selective killing of senescent cells may delay aging and/or treat age-related disorders.

First claim

What is claimed is:

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 unsubsti

Assignees

• Bioventures Llc

Inventors

• Zheng Guangrong
• Zhou Daohong
• Liu Xingui
• Wang Yingying
• Chang Jianhui
• Feng Wei
• Shao Lijian
• Luo Yi

Classifications

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title

• A61K31/635

  having a heterocyclic ring, e.g. sulfadiazine · CPC title

• C07D401/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• A61K31/45 Primary

  having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide · CPC title

• A61K31/4545

  containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine · CPC title