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 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 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 α and the bond between R 4 and L is indicated by ß:
where R 5 is H or CH 3 .
2. The compound of claim 1 ,
where BCL is:
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
where E3 is selected from one of the following:
3. The compound of claim 1 ,
where BCL is:
where R 1 is NO 2 or SO 2 CF 3 ;
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
where E3 is selected from one of the following:
4. The compound of claim 3 , 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.
5. The compound of claim 4 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.
6. The compound of claim 1 where,
BCL is:
where R 1 is NO 2 or SO 2 CF 3 ;
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
Where E3 is selected from one of the following:
7. The compound of claim 6 , 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.
8. The compound of claim 7 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.
9. The compound of claim 2 , 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.
10. The compound of claim 9 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.
11. The compound of claim 1 ,
where BCL is:
where R 1 is NO 2 or SO 2 CF 3 ;
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
where R 3 is selected from one of the following:
where E3 is selected from one of the following:
12. The compound of claim 11 , 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.
13. The compound of claim 12 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.
14. The compound of claim 1 where, BCL is:
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
.
15. The compound of claim 14 , 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.
16. The compound of claim 15 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.
17. 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 H or
where R 3 is selected from one of the following:
where R 4 is selected from one of the following, wherein the bond between R 4 and the remainder of BCL is indicated by α and the bond between R 4 and L is indicated by ß:
where R 5 is H or CH 3 .
18. The compound of claim 17 , 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.
19. The compound of claim 18 , where the linker contains only unbranched alkyl, heterocyclic, or amide groups.