HSP90-targeting conjugates and formulations thereof
Conjugates of an active agent attached to a targeting moiety, such as an HSP90 binding moiety, via a linker, and particles comprising such conjugates have been designed. Such conjugates and particles can provide improved temporospatial delivery of the active agent, improved biodistribution and penetration in tumor, and/or decreased toxicity. Methods of making the conjugates, the particles, and the formulations thereof are provided. Methods of administering the formulations to a subject in need thereof are provided, for example, to treat or prevent cancer.
1. A conjugate comprising an active agent coupled, via a linker, to an HSP90 targeting moiety, wherein the active agent is a PI3K inhibitor and the HSP90 targeting moiety is ganetespib or its derivative/analog and is selected from the group consisting of:
2. The conjugate of claim 1 , wherein the linker comprises an ester group, a disulfide group, an amide group, an acylhydrazone group, an ether group, a carbamate group, a carbonate group, or a urea group.
3. The conjugate of claim 1 , wherein the linker is a cleavable linker.
4. The conjugate of claim 1 , wherein the conjugate has a molecular weight of less than 2000 Da.
5. The conjugate of claim 1 , wherein the PI3K inhibitor is selected from the group consisting of Omipalisib (GSK458), BAY 80-6946 (Copanlisib), PF-04691502 and PI-103.
6. The conjugate of claim 5 , wherein the PI3K inhibitor is PI-103.
7. The conjugate of claim 6 , wherein the conjugate is selected from the group consisting of:
8. The conjugate of claim 5 , wherein the PI3K inhibitor is PF-04691502.
9. The conjugate of claim 8 , wherein the conjugate is:
10. A pharmaceutical composition comprising the conjugate of claim 1 and at least one pharmaceutically acceptable pharmaceutical excipient.
11. A method of reducing cell proliferation comprising administering a therapeutically effective amount of at least one conjugate of claim 1 to the cell.
12. The method of claim 11 , wherein the cell is a cancer cell.
13. The method of claim 12 , wherein the cancer cell is a small-cell lung cancer cell, a non-small-cell lung cancer cell, a sarcoma cell, a pancreatic cancer cell, a breast cancer cell, or a colon cancer cell.
14. A method of inducing apoptosis in a cell, comprising administering a therapeutically effective amount of at least one conjugate of claim 1 to the cell.
15. The method of claim 14 , wherein Caspase-9 level in the cell is increased.
16. The method of claim 14 , wherein the cell is a cancer cell.
17. The method of claim 16 , wherein the cancer cell is a small-cell lung cancer cell, a non-small-cell lung cancer cell, a sarcoma cell, a pancreatic cancer cell, a breast cancer cell, or a colon cancer cell.
18. A method of delivering an active agent to a tumor or treating a tumor comprising administering a therapeutically effective amount of at least one conjugate of claim 1 to the tumor.
19. The method of claim 18 , wherein the tumor is small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.