COMPOSITIONS TARGETING SENESCENT CELLS AND THE USES THEREOF
The present disclosure provides compositions and methods for selectively killing senescent cells, wherein the composition comprises a compound of Formula (I) or a compound of Formula (II). The selective killing of senescent cells may delay aging and/or treat age-related disorders.
1 . A method of treating chemotherapy induced peripheral neuropathy in a subject in need thereof, the method comprising administering a therapeutically-effective amount of at least one senolytic agent.
2 . The method of claim 1 , wherein the at least one senolytic agent selectively kills senescent cells over non-senescent cells.
3 . The method of claim 1 , wherein the senolytic agent is administered in at least two treatment cycles.
4 . The method of claim 3 , wherein the treatment cycle independently comprises a treatment course of from 1 day to 3 months followed by a non-treatment intervals of at least 2 weeks.
5 . The method of claim 1 , wherein the senolytic agent is a specific inhibitor of Bcl-xL, MDM2, or Akt.
6 . The method of claim 1 , wherein the senolytic agent is a means for inhibiting Bcl-xL or Bcl-2.
7 . The method of claim 1 , wherein the senolytic agent is ABT263.
8 . The method of claim 1 , wherein the senolytic agent is administered locally at or near the site of the disease.
9 . The method of claim 1 , wherein the step of administering is intravenous, intraperitoneal, subcutaneous, intramuscular, topical, transdermal or oral.
10 . The method of claim 1 , wherein the senolytic agent is a compound comprising Formula (II):
wherein
R 1 is selected from the group consisting of:
R 3 is absent, a bond, or a substituted or unsubstituted C 1 -C 10 alkyl;
A is absent, a bond, a substituted or unsubstituted C 1 -C 6 aryl, a substituted or unsubstituted C 1 -C 6 cycloalkyl, or a substituted or unsubstituted C 1 -C 6 heterocyclic group;
R 4 is a bond or a substituted or unsubstituted C 1 -C 10 alky;
n is an integer from 0 to 5,
R 2 is selected from the group consisting of
11 . The method of claim 10 , wherein R 1 is selected from the group consisting of:
12 . A method of selectively killing one or more senescent bone cells in a sample or subject in need thereof, the method comprising administering to the sample or subject a composition comprising a therapeutically effective amount of a compound comprising Formula (II):
wherein
R 1 is selected from the group consisting of:
R 3 is absent, a bond, or a substituted or unsubstituted C 1 -C 10 alkyl;
A is absent, a bond, a substituted or unsubstituted C 1 -C 6 aryl, a substituted or unsubstituted C 1 -C 6 cycloalkyl, or a substituted or unsubstituted C 1 -C 6 heterocyclic group;
R 4 is a bond or a substituted or unsubstituted C 1 -C 10 alky;
n is an integer from 0 to 5,
R 2 is selected from the group consisting of
13 . The method of claim 12 , wherein the bone cells include senescent osteoprogenitors and/or osteocytes.
14 . The method of claim 12 , wherein there is an increase osteoblast number in the sample or subject.
15 . The method of claim 12 , wherein the subject is free of thrombocytopenia following administration.
16 . A method of treating or preventing osteoporosis in subject in need thereof, the method comprising administering to the sample or subject a composition comprising a therapeutically effective amount of a compound comprising Formula (II):
wherein
R 1 is selected from the group consisting of:
R 3 is absent, a bond, or a substituted or unsubstituted C 1 -C 10 alkyl;
A is absent, a bond, a substituted or unsubstituted C 1 -C 6 aryl, a substituted or unsubstituted C 1 -C 6 cycloalkyl, or a substituted or unsubstituted C 1 -C 6 heterocyclic group;
R 4 is a bond or a substituted or unsubstituted C 1 -C 10 alky;
n is an integer from 0 to 5,
R 2 is selected from the group consisting of
17 . The method of claim 16 , wherein the subject is free of thrombocytopenia following administration.