Degradation of protein kinases by conjugation of protein kinase inhibitors with E3 ligase ligand and methods of use
The present application provides bifunctional compounds of Formula (I): or an enantiomer, diastereomer, or stereoisomer thereof, or pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof, which act as protein degradation inducing moieties for protein kinases (e.g., Bcr-Abl). The present application also relates to methods for the targeted degradation of one or more protein kinases through the use of the bifunctional compounds that link a ubiquitin ligase-binding moiety to a ligand that is capable of binding to one or more protein kinases which can be utilized in the treatment of disorders modulated by protein kinases.
1. A bifunctional compound
or a stereoisomer or pharmaceutically acceptable salt thereof,
wherein the bifunctional compound is of Formula I-1, I-2, I-3, I-4, I-5, I-6, I-7, I-8, I-10, I-11, or I-12:
2. A pharmaceutical composition comprising a therapeutically effective amount of the bifunctional compound of claim 1 , or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
3. A method of inhibiting the activity of at least protein kinase Bcr-Abl, comprising administering to a subject in need thereof an effective amount of the compound or a stereoisomer or pharmaceutically acceptable salt thereof of claim 1 .
4. A method of treating a cancer in which at least protein kinase Bcr-Abl plays a role, wherein the cancer is leukemia, rhabdomyosarcoma or lymphoma, comprising administering to a subject in need thereof an effective amount of the compound or a stereoisomer or pharmaceutically acceptable salt thereof of claim 1 .
5. The method of claim 4 , wherein the cancer is leukemia.
6. The method of claim 5 , wherein the leukemia is adult T-cell leukemia/lymphoma (ATLL), acute nonlymphocytic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, acute myelogenous leukemia, acute lymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acute-myeloid leukemia (AML), or chronic myeloid leukemia (CML).
7. The method of claim 4 , wherein the cancer is rhabdomyosarcoma.
8. The method of claim 4 , wherein the cancer is lymphoma.
9. The bifunctional compound of claim 1 , wherein the structure is of Formula I-1:
(I-1), or a stereoisomer or pharmaceutically acceptable salt thereof.
10. The bifunctional compound of claim 1 , wherein the structure is of Formula I-2:
stereoisomer or pharmaceutically acceptable salt thereof.
11. The bifunctional compound of claim 1 , wherein the structure is of Formula I-3:
(I-3), or a stereoisomer or pharmaceutically acceptable salt thereof.
12. The bifunctional compound of claim 1 , wherein the structure is of Formula I-4:
(I-4), or a stereoisomer or pharmaceutically acceptable salt thereof.
13. The bifunctional compound of claim 1 , wherein the structure is of Formula I-5:
(I-5), or a stereoisomer or pharmaceutically acceptable salt thereof.
14. The bifunctional compound of claim 1 , wherein the structure is of Formula I-6:
(I-6), or a stereoisomer or pharmaceutically acceptable salt thereof.
15. The bifunctional compound of claim 1 , wherein the structure is of Formula I-7:
(I-7), or a stereoisomer or pharmaceutically acceptable salt thereof.
16. The bifunctional compound of claim 1 , wherein the structure is of Formula I-8:
(I-8), or a stereoisomer or pharmaceutically acceptable salt thereof.
17. The bifunctional compound of claim 1 , wherein the structure is of Formula I-10:
(I-10), or a stereoisomer or pharmaceutically acceptable salt thereof.
18. The bifunctional compound of claim 1 , wherein the structure is of Formula I-11:
(I-11), or a stereoisomer or pharmaceutically acceptable salt thereof.
19. The bifunctional compound of claim 1 , wherein the structure is of Formula I-12:
(I-12), or a stereoisomer or pharmaceutically acceptable salt thereof.