TARGETED THERAPEUTICS
The present invention provides pharmacological compounds including an effector moiety conjugated to an 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.
2 . The SDC-TRAP of claim 1 , wherein the binding moiety interacts with a protein that is overexpressed in cancerous cells compared to normal cells.
3 . The SDC-TRAP of claim 2 , wherein the protein is a chaperonin protein.
4 . The SDC-TRAP of claim 3 , wherein the chaperonin is Hsp90.
5 . The SDC-TRAP of claim 4 , wherein the binding moiety is an Hsp90 ligand or a prodrug thereof.
6 . The SDC-TRAP of claim 5 , wherein the Hsp90 ligand is an Hsp90 inhibitor.
7 . The SDC-TRAP of claim 6 , wherein the Hsp90 inhibitor is selected from the group consisting of geldanamycins, macbecins, tripterins, tanespimycins, and radicicols.
8 . The SDC-TRAP of claim 1 , wherein the effector moiety is an imaging moiety.
9 . The SDC-TRAP of claim 1 , wherein the effector moiety is a therapeutic moiety.
10 . The SDC-TRAP of claim 9 , wherein the therapeutic moiety is a cytotoxic moiety.
11 . The SDC-TRAP of claim 10 , wherein the cytotoxic moiety is SN-38, Bendamustine, VDA, Doxorubicin, Pemetrexed, Vorinostat, Lenalidomide, irinotecan, ganetespib, Docetaxel, 17AAG, 5FU, Vorinostat, Abiraterone, Crizotinib, or fragment thereof.
12 . The SDC-TRAP of claim 10 , wherein the cytotoxic moiety is not suitable for administration alone.
13 . The SDC-TRAP of claim 12 , wherein the cytotoxic moiety is not suitable for administration alone due to toxicity.
14 . The SDC-TRAP of claim 5 , wherein the molecular weight of the SDC-TRAP is less than about 1600 Daltons.
15 . The SDC-TRAP of claim 14 , wherein the molecular weight of the SDC-TRAP is less than about 1200 Daltons.
16 . The SDC-TRAP of claim 14 , wherein the molecular weight of the SDC-TRAP is less than about 800 Daltons.
17 . The SDC-TRAP of claim 14 , wherein the molecular weight of the SDC-TRAP is less than about 600 Daltons.
18 . The SDC-TRAP of claim 14 , wherein the molecular weight of the SDC-TRAP is less than about 400 Daltons.
19 . The SDC-TRAP of claim 1 , wherein the binding moiety and the effector moiety are covalently attached.
20 . The SDC-TRAP of claim 19 , wherein the binding moiety and the effector moiety are covalently attached by a linker.
21 . The SDC-TRAP of claim 20 , wherein the linker comprises a cleavable linker.
22 . The SDC-TRAP of claim 21 , wherein the cleavable linker comprises an enzymatically cleavable linker.
23 . The SDC-TRAP of claim 20 , wherein the linker is selected from the group consisting of disulfide, carbamate, amide, ester, and ether linkers.
24 . (canceled)
25 . The SDC-TRAP of claim 1 , wherein the SDC-TRAP is able to enter a cell by passive diffusion.
26 - 70 . (canceled)
71 . The SDC-TRAP of claim 1 , wherein the binding moiety has a molecular weight of less than 800, 700, 600, 500, 400, 300, or 200 Daltons.
72 - 99 . (canceled)
100 . The SDC-TRAP of claim 1 , wherein the effector moiety has a molecular weight of less than 800, 700, 600, 500, 400, 300, or 200 Daltons.
101 - 125 . (canceled)
126 . The SDC-TRAP of claim 1 , wherein the binding moiety and the effector moiety are approximately equal in size.
127 . The SDC-TRAP of claim 126 , wherein the binding moiety and the effector moiety have less than about 50, 100, 200, 300, or 400 Dalton difference in molecular weight.
128 - 150 . (canceled)
151 . The SDC-TRAP of claim 1 , wherein the binding moiety comprises an Hsp90 binding moiety and wherein the Hsp90 binding moiety interacts with the N-terminal domain of Hsp90.
152 - 170 . (canceled)
171 . The SDC-TRAP of claim 1 , wherein the binding moiety comprises an Hsp90 binding moiety and wherein the Hsp90 binding moiety interacts with the C-terminal domain of Hsp90.
172 - 190 . (canceled)
191 . The SDC-TRAP of claim 1 , wherein the binding moiety comprises an Hsp90 binding moiety and wherein the Hsp90 binding moiety interacts with the middle domain of Hsp90.
192 - 210 . (canceled)
211 . The SDC-TRAP of claim 1 , wherein the binding moiety has a K d of 100, 150, 200, or 250 nM or higher.
212 - 233 . (canceled)
234 . The SDC-TRAP of claim 1 , wherein when administered to a subject the SDC-TRAP present at a ratio of 2:1, 5:1, 10:1, 50:1, 100:1, 250:1, 500:1, or 1000:1 in tumor cells compared to plasma.
235 - 241 . (canceled)
242 . The SDC-TRAP of claim 234 , wherein the ratio is at 4, 12, 24, 48, or 72 hours from administration.
243 - 265 . (canceled)
266 . The SDC-TRAP of claim 1 , wherein the SDC-TRAP is present in cancer cells for at least 24, 48, 72, 96, or 120 hours.
267 - 289 . (canceled)
290 . The SDC-TRAP of claim 1 , wherein the effector moiety is released for a period of at least 6, 12, 24, 48, 72, or 96 hours.
291 - 314 . (canceled)
315 . The SDC-TRAP of claim 1 , wherein the effector moiety is selectively released inside a cancer cell.
316 - 354 . (canceled)
355 . The SDC-TRAP of claim 1 , wherein the binding moiety is an inhibitor that is ineffective as a therapeutic agent when administered alone.
356 - 372 . (canceled)
373 . A pharmaceutical composition comprising a therapeutically effective amount of at least one SDC-TRAP, and at least one pharmaceutical excipient.
374 . (canceled)
375 . 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.
376 - 394 . (canceled)
395 . A kit for treating a subject in need thereof comprising at least one SDC-TRAP and instruction for administering a therapeutically effective amount of the at least one SDC-TRAP to the subject, thereby treating the subject.
396 . (canceled)
397 . A method for imaging, diagnosing, and/or selecting a subject comprising administering an effective amount of at least one SDC-TRAP to the subject, thereby imaging, diagnosing, and/or selecting the subject.
398 - 416 . (canceled)
417 . A kit for imaging, diagnosing, and/or selecting a subject comprising at least one SDC-TRAP and instruction for administering an effective amount of at least one SDC-TRAP to the subject, thereby imaging, diagnosing, and/or selecting the subject.
418 . (canceled)