Targeted therapeutics
The present invention provides pharmacological compounds including an effector moiety conjugated to a binding moiety that directs the effector moiety 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 an effector moiety. For example, in certain embodiments directed to treating cancer, the SDC-TRAP can include an Hsp90 inhibitor conjugated to a cytotoxic agent as the effector moiety.
1. A binding moiety-drug conjugate (SDC-TRAP) comprising a binding moiety and an effector moiety, wherein the binding moiety binds to Hsp90 and wherein the effector moiety is a cytotoxic agent selected from the group consisting of flavopiridol, lapatinib, axitinib, vemurafenib, imatinib, staurosporine, panobinostat, carfilzomib, INCB024360 and methyl tryptophan or (a) fragment(s) thereof, and wherein the binding moiety and the effector moiety are covalently attached.
2. The SDC-TRAP of claim 1 , wherein the binding moiety is an Hsp90 ligand or a prodrug thereof.
3. The SDC-TRAP of claim 2 , wherein the Hsp90 ligand is an Hsp90 inhibitor.
4. The SDC-TRAP of claim 3 , wherein the Hsp90 inhibitor is selected from the group consisting of geldanamycins, macbecins, tripterins, tanespimycins, and radicicols.
5. The SDC-TRAP of claim 1 , wherein the molecular weight of the SDC-TRAP is less than about 1600 Daltons, less than about 1200 Daltons, less than about 800 Daltons, less than about 600 Daltons, or less than about 400 Daltons.
6. The SDC-TRAP of claim 1 , wherein the binding moiety and the effector moiety are covalently attached by a linker.
7. The SDC-TRAP of claim 6 , wherein the linker comprises a cleavable linker.
8. The SDC-TRAP of claim 7 , wherein the cleavable linker comprises an enzymatically cleavable linker.
9. The SDC-TRAP of claim 6 , wherein the linker is selected from the group consisting of disulfide, carbamate, amide, ester, and ether linkers.
10. The SDC-TRAP of claim 1 , wherein the SDC-TRAP is able to Zenter a cell by passive diffusion or by active transport.
11. The SDC-TRAP of claim 1 , wherein the binding moiety has a molecular weight of less than 800 Daltons.
12. The SCD-TRAP of claim 1 , wherein the effector moiety has a molecular weight of less than 800 Daltons.
13. A pharmaceutical composition comprising a therapeutically effective amount of at least one SDC-TRAP of claim 1 , and at least one pharmaceutical excipient.