TARGETED THERAPEUTICS
The present invention provides pharmacological compounds including a peptide epoxy ketone protease inhibitor conjugated to a binding moiety that directs the peptide epoxy ketone protease inhibitor to a biological target of interest. Likewise, the present invention provides compositions, kits, and methods (e.g., therapeutic, diagnostic, and imaging) including the compounds. The compounds can be described as a protein interacting binding moiety-drug conjugate (SDC-TRAP) compounds, which include a protein interacting binding moiety and a peptide epoxy ketone protease inhibitor. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the peptide epoxy ketone protease inhibitor.
1 .- 20 . (canceled)
21 . A SDC-TRAP comprising an Hsp90 binding moiety and a peptide epoxy ketone protease inhibitor.
22 . The SDC-TRAP of claim 21 , wherein the Hsp90 binding moiety interacts with a protein that is overexpressed in a target cell compared to a normal cell.
23 . The SDC-TRAP of claim 22 , wherein the target cell is a cancer cell.
24 . The SDC-TRAP of claim 21 , wherein the Hsp90 binding moiety is an Hsp90 ligand or a prodrug thereof.
25 . The SDC-TRAP of claim 24 , wherein the Hsp90 ligand is an Hsp90 inhibitor.
26 . The SDC-TRAP of claim 25 , wherein the Hsp90 inhibitor is selected from the group consisting of ganetespib, geldanamycins, macbecins, tripterins, tanespimycins, and radicicols.
27 . The SDC-TRAP of claim 21 , wherein the SDC-TRAP is selected from the group consisting of: SDC-TRAP-1001, SDC-TRAP-1002, SDC-TRAP-1003, SDC-TRAP-1004, SDC-TRAP-1005, SDC-TRAP-1006, SDC-TRAP-1007, SDC-TRAP-1008, SDC-TRAP-1009, SDC-TRAP-1010, SDC-TRAP-1011, SDC-TRAP-1012, SDC-TRAP-1013, SDC-TRAP-1014, SDC-TRAP-1015, SDC-TRAP-1016, SDC-TRAP-1017, SDC-TRAP-1018, SDC-TRAP-1019, SDC-TRAP-1020, SDC-TRAP-1021, SDC-TRAP-1022, SDC-TRAP-1023, SDC-TRAP-1024, SDC-TRAP-1025, SDC-TRAP-1026, SDC-TRAP-10127, SDC-TRAP-1028, SDC-TRAP-1029, SDC-TRAP-1030, SDC-TRAP-1031, SDC-TRAP-1032, SDC-TRAP-1033 and SDC-TRAP-1034.
28 . The SDC-TRAP of claim 21 , wherein the SDC-TRAP exhibits decreased toxicity and increased efficacy compared to the Hsp90 binding moiety or peptide epoxy ketone protease inhibitor used alone.
29 . The SDC-TRAP of claim 22 , wherein the SDC-TRAP is present in a target cell for at least 24 hours.
30 . The SDC-TRAP of claim 22 , wherein the SDC-TRAP is released in a target cell for at least 6 hours.
31 . The SDC-TRAP of claim 21 , wherein the Hsp90 binding moiety and the peptide epoxy ketone protease inhibitor are covalently attached.
32 . The SDC-TRAP of claim 31 , wherein the Hsp90 binding moiety and the peptide epoxy ketone protease inhibitor are covalently attached by a linker.
33 . The SDC-TRAP of claim 32 , wherein the linker comprises a cleavable linker.
34 . The SDC-TRAP of claim 33 , wherein the cleavable linker comprises an enzymatically cleavable linker.
35 . The SDC-TRAP of claim 32 , wherein the linker is selected from the group consisting of disulfide, carbamate, amide, ester, and ether linkers.
36 . The SDC-TRAP of claim 21 , wherein the SDC-TRAP is able to enter a cell by passive diffusion or active transport.
37 . The SDC-TRAP of claim 21 , wherein the peptide epoxy ketone protease inhibitor is carfilzomib or its fragment or analog.
38 .- 55 . (canceled)
56 . A pharmaceutical composition comprising a therapeutically effective amount of at least one SDC-TRAP, and at least one pharmaceutical excipient, wherein the SDC-TRAP comprises the SDC-TRAP of claim 21 .
57 .- 58 . (canceled)
59 . The pharmaceutical composition of claim 56 , wherein the SDC-TRAP is selected from the group consisting of: SDC-TRAP-1001, SDC-TRAP-1002, SDC-TRAP-1003, SDC-TRAP-1004, SDC-TRAP-1005, SDC-TRAP-1006, SDC-TRAP-1007, SDC-TRAP-1008, SDC-TRAP-1009, SDC-TRAP-1010, SDC-TRAP-1011, SDC-TRAP-1012, SDC-TRAP-1013, SDC-TRAP-1014, SDC-TRAP-1015, SDC-TRAP-1016, SDC-TRAP-1017, SDC-TRAP-1018, SDC-TRAP-1019, SDC-TRAP-1020, SDC-TRAP-1021, SDC-TRAP-1022, SDC-TRAP-1023, SDC-TRAP-1024, SDC-TRAP-1025, SDC-TRAP-1026, SDC-TRAP-10127, SDC-TRAP-1028, SDC-TRAP-1029, SDC-TRAP-1030, SDC-TRAP-1031, SDC-TRAP-1032, SDC-TRAP-1033 and SDC-TRAP-1034.
60 . A method for treating a subject in need thereof comprising administering a therapeutically effective amount of at least one SDC-TRAP to the subject, thereby treating the subject, wherein the SDC-TRAP comprises the SDC-TRAP of claim 21 .
61 . (canceled)
62 . The method of claim 60 , wherein the subject is suffering from a disease of disorder selected from the group consisting of: cancer, autoimmune disease, graft or transplant-related condition, neurodegenerative disease, fibrotic-associated condition, ischemic-related conditions, infection (viral, parasitic or prokaryotic) and diseases associated with bone loss.
63 . The method of claim 62 , wherein the subject is suffering from cancer.
64 .- 67 . (canceled)
68 . A kit for imaging, diagnosing, and/or selecting a subject comprising at least one SDC-TRAP and instructions for administering an effective amount of the at least one SDC-TRAP to the subject, thereby imaging, diagnosing, and/or selecting the subject, wherein the SDC-TRAP comprises the SDC-TRAP of claim 21 .
69 .- 71 . (canceled)