Compounds that induce degradation of anti-apoptotic Bcl-2 family proteins 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. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where R 1 is NO 2 or SO 2 CF 3 ;
where R 2 is one of the following:
where R 3 is one of the following:
where R 4 is one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by a and the bond between R 4 and L is indicated by β:
where E3 has one of the following structures:
where R 6 and R 7 are both
or R 6 is
and R 7 is H.
2. The compound of claim 1 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
3. The compound of claim 1 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
4. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where BCL is the portion of the structure depicted to the left of L and E3 is the portion of the structure depicted to the right of L;
where R 1 is NO 2 or SO 2 CF 3 ;
where R 2 is
where R 3 is one of the following:
where R 4 is one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by a and the bond between R 4 and L is indicated by β:
where R 5 is H or CH 3 .
5. The compound of claim 4 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
6. The compound of claim 4 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
7. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where BCL is the portion of the structure depicted to the left of L and E3 is the portion of the structure depicted to the right of L;
where R 1 is NO 2 or SO 2 CF 3 ;
where R 2 is
where R 4 is one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by a and the bond between R 4 and L is indicated by β:
where R 5 is H or CH 3 .
8. The compound of claim 7 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
9. The compound of claim 7 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
10. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where R 4 is one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by a and the bond between R 4 and L is indicated by β:
where R 5 is H or CH 3 .
11. The compound of claim 10 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
12. The compound of claim 10 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
13. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where R 5 is H or CH 3 ;
where BCL is one of the following:
14. The compound of claim 13 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
15. The compound of claim 13 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
16. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where R 5 is H or CH 3 ;
where BCL is one of the following:
17. The compound of claim 16 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
18. The compound of claim 16 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.
19. The compound of the formula:
BCL-L-E3
wherein,
BCL is a protein targeting unit which binds to one or more anti-apoptotic Bcl-2 family proteins;
E3 is an E3 ubiquitin ligase binding unit which binds to the CRBN or VHL E3 ubiquitin ligase; and
L is a linker unit with two ends, each of which covalently links to one of BCL and E3 through one or more of the following functional groups: alkyl, branched alkyl, ether, thioether, ester, amine, amide, carbamate, carbamide, sulfone, aryl, heteroaryl, cycloalkyl, or heterocycle;
wherein the linker comprises two ends, wherein each of the two ends are the same or different;
wherein the linker unit comprises a length of 1-30 atoms, and
wherein the compound has the following chemical structure:
where R 5 is H or CH 3 ;
where BCL is one of the following:
20. The compound of claim 19 , where the length of the linker is 5-7 atoms in length and the linker contains only alkyl, branched alkyl, heterocyclic, ether, or amide groups.
21. The compound of claim 19 , where L is
where the bond between L and BCL is indicated by δ and the bond between L and E3 is indicated by ε and n=0-6.