Hsp90-targeting conjugates and formulations thereof

Abstract

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.

We claim: 
     
         1 . A conjugate comprising an active agent coupled, via a linker, to an HSP90 targeting moiety. 
     
     
         2 . The conjugate of  claim 1 , wherein the active agent is selected from the group consisting of DM1, MMAE, PBD or PBD dimer, a PARP inhibitor, or a PI3K inhibitor. 
     
     
         3 . The conjugate of  claim 2 , wherein the PARP inhibitor is selected from the group consisting of olaparib, veliparib (ABT-888), rucaparib (AG014699 or PF-01367338), ganetespib, talazoparib (BMN673), niraparib, iniparib (BSI 201), CEP 9722, E7016, BGB-290, and derivatives/analogs thereof. 
     
     
         4 . The conjugate of  claim 2 , wherein the PI3K inhibitor is selected from the group consisting of Omipalisib (GSK2126458, GSK458), BAY 80-6946 (Copanlisib), PF-04691502, PI-103, BGT226 (NVP-BGT226), Apitolisib (GDC-0980, RG7422), Duvelisib (IPI-145, INK1197), AZD8186, Pilaralisib (XL147), PIK-93, Idelalisib (GS-1101), MLN1117, VS-5584, SB2343, GDC-0941, BM120, NVP-BKM120, Buparlisib, AZD8835, XL765 (SAR245409), GS-9820 Acalisib, GSK2636771, AMG-319, IPI-549, Perifosine, Alpelisib, TGR 1202 (RP5264), PX-866, and derivatives/analogs thereof. 
     
     
         5 . The conjugate of  claim 1 , wherein the HSP90 targeting moiety is an HSP90 inhibitor. 
     
     
         6 . The conjugate of  claim 5 , wherein the HSP90 inhibitor is a small molecule. 
     
     
         7 . The conjugate of  claim 6 , wherein the HSP90 inhibitor is selected from the group consisting of Ganetespib, Luminespib (AUY-922, NVP-AUY922), Debio-0932, MPC-3100, or Onalespib (AT-13387), SNX-2112, 17-amino-geldanamycin hydroquinone, PU-H71, AT13387, and derivatives/analogs thereof. 
     
     
         8 . The conjugate of  claim 7 , wherein the HSP90 inhibitor is ganetespib, TM1, TM2, TM3, TM4 or TM5. 
     
     
         9 . 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. 
     
     
         10 . The conjugate of  claim 1 , wherein the linker is a cleavable linker. 
     
     
         11 . The conjugate of  claim 1 , wherein the conjugate has a molecular weight of less than about 50,000 Da, less than about 40,000 Da, less than about 30,000 Da, less than about 20,000 Da, less than about 15,000 Da, less than about 10,000 Da, less than about 8,000 Da, less than about 5,000 Da, less than about 3,000 Da, less than 2000 Da, less than 1500 Da, less than 1000 Da, or less than 500 Da. 
     
     
         12 . The conjugate of  claim 1 , wherein the conjugate comprises DM1 or its derivative/analog and ganetespib or its derivative/analog. 
     
     
         13 . The conjugate of  claim 12 , wherein the conjugate is selected from the group consisting of Compound 1, Compound 2, Compound 3, and Compound 14. 
     
     
         14 . The conjugate of  claim 1 , wherein the conjugate comprises a PARP inhibitor and ganetespib or its derivative/analog. 
     
     
         15 . The conjugate of  claim 14 , wherein the PARP inhibitor is olaparib or its derivative/analog. 
     
     
         16 . The conjugate of  claim 15 , wherein the conjugate has a structure of 
       
         
           
           
               
               
           
         
         wherein R′ is H or any other substituents. 
       
     
     
         17 . The conjugate of  claim 16 , wherein R′ is H and the conjugate is Compound 4. 
     
     
         18 . The conjugate of  claim 16 , wherein R′ is not hydrogen. 
     
     
         19 . The conjugate of  claim 18 , wherein R′ is —CH 2 CH 2 NMe 2  and the conjugate is Compound 5. 
     
     
         20 . The conjugate of  claim 15 , wherein the conjugate has a structure of 
       
         
           
           
               
               
           
         
         wherein R′ is H or any other substituents. 
       
     
     
         21 . The conjugate  claim 20 , wherein R′ is not hydrogen. 
     
     
         22 . The conjugate of  claim 21 , wherein R′ is —CH 2 CH 2 NMe 2  and the conjugate is Compound 6. 
     
     
         23 . The conjugate of  claim 15 , wherein the conjugate is Compound 7 or Compound 8. 
     
     
         24 . The conjugate of  claim 14 , wherein the PARP inhibitor is Talazoparib or its derivative/analog. 
     
     
         25 . The conjugate of  claim 24 , wherein the conjugate is Compound 9. 
     
     
         26 . The conjugate of  claim 1 , wherein the conjugate comprises a PI3K inhibitor and ganetespib or its derivative/analog. 
     
     
         27 . The conjugate of  claim 26 , wherein the PI3K inhibitor is selected from the group consisting of Omipalisib (GSK458) or its derivative/analog, BAY 80-6946 (Copanlisib) or its derivative/analog, PF-04691502 or its derivative/analog, and PI-103 or its derivative/analog. 
     
     
         28 . The conjugate of  claim 27 , wherein the PI3K inhibitor is PI-103. 
     
     
         29 . The conjugate of  claim 28 , wherein the conjugate is Compounds 10, Compound 12, or Compound 13. 
     
     
         30 . The conjugate of  claim 27 , wherein the PI3K inhibitor is PF-04691502. 
     
     
         31 . The conjugate of  claim 30 , wherein the conjugate is Compound 11. 
     
     
         32 . The conjugate of  claim 1 , wherein the conjugate comprises MMAE or its derivative/analog and ganetespib or its derivative/analog. 
     
     
         33 . The conjugate of  claim 32 , wherein the conjugate is selected from the group consisting of Compound 15 and Compound 16. 
     
     
         34 . A pharmaceutical composition comprising the conjugate of  claim 1  and at least one pharmaceutically acceptable excipient. 
     
     
         35 . A method of reducing cell proliferation comprising administering a therapeutically effective amount of at least one conjugate of  claim 1  to the cell. 
     
     
         36 . The method of  claim 35 , wherein the cell is a cancer cell. 
     
     
         37 . The method of  claim 36 , 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. 
     
     
         38 . 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. 
     
     
         39 . The method of  claim 38 , wherein Caspase-9 level in the cell is increased. 
     
     
         40 . The method of  claim 38 , wherein the cell is a cancer cell. 
     
     
         41 . The method of  claim 40 , 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. 
     
     
         42 . 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. 
     
     
         43 . The method of  claim 42 , wherein the active agent is DM1, MMAE, PBD or PBD dimer, a PARP inhibitor, or a PI3K inhibitor. 
     
     
         44 . The method of  claim 42 , wherein the tumor is small-cell lung cancer, non-small-cell lung cancer, sarcoma, pancreatic cancer, breast cancer, or colon cancer.