Synthesis of small molecule histone deacetylase 6 degraders, compounds formed thereby, and pharmaceutical compositions containing them
Histone deacetylase (“HDAC”)-selective inhibitors covalently bonded to a linker covalently bonded to an E3 ubiquitin ligase ligand, and salts thereof; pharmaceutical compositions containing them; methods of using the composition to inhibit neoplastic cell growth in mammals, including humans.
1. A compound comprising a histone deacetylase 6 (“HDAC 6 ”)-selective inhibitor covalently bonded to a linker, covalently bonded to an E3 ubiquitin ligase ligand:
wherein:
the HDAC 6 -selective inhibitor is selected from the group consisting of:
wherein each Z is independently selected from —N— or —(CH);
the linker is a C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene, —O—(CH 2 ) n —, or —NH—(CH 2 ) n , wherein “n” is an integer of from 1 to 12; and
the E3 ubiquitin ligase ligand is selected from:
wherein R 3 is hydrogen, C 1 —C 6 —alkyl, or ═O, R 4 is hydrogen or halogen, Y is —(C═O)— or —(CH 2 )—, and “m” is an integer of from 1 to 6; and
salts thereof.
2. The compound of claim 1 , wherein the linker is C 1 -C 12 linear or branched alkylene, alkenylene, or alkynylene.
3. The compound of claim 2 , wherein each Z is —N—.
4. The compound of claim 2 , wherein each Z is —(CH)—.
5. The compound of claim 2 , wherein Y is —(C═O)—.
6. The compound of claim 2 , wherein Y is —(CH 2 )—.
7. The compound of claim 1 , wherein the linker is —NH—(CH 2 ) n .
8. The compound of claim 7 , wherein each Z is —N—.
9. The compound of claim 7 , wherein each Z is —(CH)—.
10. The compound of claim 7 , wherein Y is —(C═O)—.
11. The compound of claim 7 , wherein Y is —(CH 2 )—.
12. The compound of claim 1 , wherein the linker —NH—(CH 2 ) n .
13. The compound of claim 12 , wherein each Z is —N—.
14. The compound of claim 12 , wherein each Z is —(CH)—.
15. The compound of claim 12 , wherein Y is —(C═O)—.
16. The compound of claim 12 , wherein Y is —(CH 2 )—.
17. The compound of claim 1 , wherein the HDAC 6 -selective inhibitor is:
and
the E3 ubiquitin ligase ligand is selected from:
18. The compound of claim 17 , wherein each Z is —N—.
19. The compound of claim 17 , wherein each Z is —(CH)—.
20. The compound of claim 17 , wherein Y is —(C═O)—.
21. The compound of claim 17 , wherein Y is —(CH 2 )—.
22. The compound of claim 17 , wherein the E3 ubiquitin ligase ligand is selected from:
wherein Y is —(C═O)—.
23. The compound of claim 17 , wherein the E3 ubiquitin ligase ligand is selected from:
wherein Y is —(CH 2 )—.
24. The compound of claim 17 , wherein the E3 ubiquitin ligase ligand is selected from:
wherein Y is —(C═O)—.
25. The compound of claim 17 , wherein the E3 ubiquitin ligase ligand is selected from:
wherein Y is —(CH 2 )—.
26. A method to inhibit neoplastic cell growth, the method comprising contacting a cell with one or more compounds as recited in claim 1 , wherein the neoplastic cell is selected from the group consisting of multiple myeloma, malignant melanoma, and leukemia.
27. A method to inhibit neoplastic cell growth, the method comprising administering to a subject a neoplastic cell growth inhibiting-effective amount of one or more compounds as recited in claim 1 , wherein the neoplastic cell is selected from the group consisting of multiple myeloma, malignant melanoma, and leukemia.
28. A pharmaceutical composition comprising an amount of one or more compounds as recited in claim 1 , in combination with a pharmaceutically suitable carrier.