US2020316090A1PendingUtilityA1

Targeted therapeutics

71
Assignee: MADRIGAL PHARMACEUTICALS INCPriority: Apr 16, 2012Filed: May 26, 2020Published: Oct 8, 2020
Est. expiryApr 16, 2032(~5.7 yrs left)· nominal 20-yr term from priority
Inventors:Dinesh U. ChimmanamadaWeiwen Ying
G01N 33/57595G01N 33/575A61P 35/00A61K 31/4184A61K 31/506A61K 31/519A61K 31/513A61K 31/437A61K 47/55A61K 31/4196A61K 31/167A61K 31/185A61K 31/58A61K 31/4545A61K 31/496A61K 31/704A61K 31/4745A61K 47/54A61K 31/454A61K 31/565A61K 47/545A61K 47/50G01N 33/57496G01N 33/574
71
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Claims

Abstract

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.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A binding moiety-drug conjugate (SDC-TRAP) comprising a binding moiety and an effector moiety, wherein the binding moiety binds to HSP90 and the effector moiety is a cytotoxic moiety. 
     
     
         2 . The SDC-TRAP of  claim 1 , wherein the binding moiety comprises an HSP90 inhibitor. 
     
     
         3 . The SDC-TRAP of  claim 2 , wherein the HSP90 inhibitor is selected from the group consisting of ganetespib, geldanamycin (tanespimycin), IPI-493, macbecins, tripterins, tanespimycins, 17-AAG (alvespimycin), KF-55823, radicicols, KF-58333, KF-58332, 17-DMAG, IPI-504, BIM-021, BIIB-028, PU-H64, PU-H71, PU-DZ8, PU-HZ151, SNX-2112, SNX-2321, SNX-5422, SNX-7081, SNX-8891, SNX-0723, SAR-567530, ABI-287, ABI-328, AT-13387, NSC-113497, PF-3823863, PF-4470296, EC-102, EC-154, ARQ-250-RP, BC-274, VER-50589, KW-2478, BHI-001, AUY-922, EMD-614684, EMD-683671, XL-888, VER-51047, KOS-2484, KOS-2539, CUDC-305, MPC-3100, CH-5164840, PU-DZ13, PU-HZ151, PU-DZ13, VER-82576, VER-82160, VER-82576, VER-82160, NXD-30001, NVP-HSP990, SST-0201CL1, SST-0115AA1, SST-0221AA1, SST-0223AA1, novobiocin, herbinmycin A, radicicol, CCT018059, PU-H71, celastrol, or a tautomer thereof. 
     
     
         4 . The SDC-TRAP of  claim 1 , wherein the binding moiety and the effector moiety are covalently attached by a bond or a linker. 
     
     
         5 . The SDC-TRAP of  claim 4 , wherein the bond or the linker is cleavable. 
     
     
         6 . The SDC-TRAP of  claim 4 , wherein the bond or linker comprises disulfide, carbamate, amide, ester, or ether. 
     
     
         7 . The SDC-TRAP of  claim 1 , wherein the molecular weight of the SDC-TRAP is less than about 1600 Daltons, about 1200 Daltons, about 800 Daltons, about 600 Daltons, about 500 Daltons, about 400 Daltons, or about 300 Daltons. 
     
     
         8 . The SDC-TRAP of  claim 1 , wherein the cytotoxic moiety is a small molecule. 
     
     
         9 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises SN-38 or irinotecan, or a fragment or analog thereof. 
     
     
         10 . The SDC-TRAP of  claim 9 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0011, SDC-TRAP-0012, SDC-TRAP-0014, SDC-TRAP-0063, SDC-TRAP-0064, SDC-TRAP-0065, SDC-TRAP-0066, SDC-TRAP-0084, SDC-TRAP-0086, SDC-TRAP-0088, SDC-TRAP-0087, SDC-TRAP-0089, SDC-TRAP-0090, SDC-TRAP-0091, SDC-TRAP-0092, SDC-TRAP-0104, SDC-TRAP-0106, SDC-TRAP-0107, SDC-TRAP-0145, SDC-TRAP-0204, SDC-TRAP-0207, SDC-TRAP-0206, SDC-TRAP-0205, SDC-TRAP-0208, SDC-TRAP-0209, SDC-TRAP-0210, SDC-TRAP-0213, SDC-TRAP-0214, SDC-TRAP-0215, SDC-TRAP-0216, SDC-TRAP-0217, SDC-TRAP-0218, SDC-TRAP-0027, SDC-TRAP-0028, SDC-TRAP-0029, SDC-TRAP-0037, SDC-TRAP-0038, SDC-TRAP-0046, SDC-TRAP-0047, SDC-TRAP-0067, SDC-TRAP-0070, SDC-TRAP-0077, SDC-TRAP-0079, SDC-TRAP-0081, SDC-TRAP-0083, SDC-TRAP-0094, SDC-TRAP-0095, SDC-TRAP-0101, SDC-TRAP-0220, SDC-TRAP-0010, SDC-TRAP-0023, SDC-TRAP-0024, SDC-TRAP-0026, SDC-TRAP-0042, SDC-TRAP-0043, SDC-TRAP-0044, SDC-TRAP-0045, SDC-TRAP-0055, SDC-TRAP-0056, SDC-TRAP-0057, SDC-TRAP-0058, SDC-TRAP-0060, SDC-TRAP-0061, SDC-TRAP-0071, SDC-TRAP-0072, SDC-TRAP-0073, SDC-TRAP-0074, SDC-TRAP-0075, SDC-TRAP-0076, SDC-TRAP-0097, SDC-TRAP-0100, SDC-TRAP-0111, SDC-TRAP-0112, SDC-TRAP-0113, SDC-TRAP-0154, SDC-TRAP-0169, SDC-TRAP-0172, SDC-TRAP-0180, SDC-TRAP-0181, SDC-TRAP-0184, SDC-TRAP-0185, SDC-TRAP-0186, SDC-TRAP-0201, SDC-TRAP-0202, SDC-TRAP-0203, SDC-TRAP-0221, and SDC-TRAP-0222. 
     
     
         11 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises lenalidomide or a fragment or analog thereof. 
     
     
         12 . The SDC-TRAP of  claim 11 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0105, SDC-TRAP-0108, SDC-TRAP-0126, SDC-TRAP-0132, SDC-TRAP-0127, SDC-TRAP-0133, SDC-TRAP-0135, SDC-TRAP-0140, SDC-TRAP-0136, SDC-TRAP-0231, SDC-TRAP-0147, SDC-TRAP-0165, SDC-TRAP-0163, SDC-TRAP-0164, SDC-TRAP-0166, SDC-TRAP-0188, SDC-TRAP-0189, SDC-TRAP-0190, SDC-TRAP-0191, SDC-TRAP-0192, SDC-TRAP-0193, SDC-TRAP-0122, SDC-TRAP-0123, SDC-TRAP-0124, SDC-TRAP-0125, SDC-TRAP-0155, SDC-TRAP-0156, SDC-TRAP-0157, SDC-TRAP-0160, SDC-TRAP-0167, SDC-TRAP-0168, SDC-TRAP-0170, SDC-TRAP-0171, SDC-TRAP-0182, SDC-TRAP-0187, SDC-TRAP-0017, SDC-TRAP-0015, SDC-TRAP-0018, SDC-TRAP-0021, SDC-TRAP-0033, SDC-TRAP-0041, SDC-TRAP-0109, SDC-TRAP-0110, SDC-TRAP-0114, SDC-TRAP-0115, SDC-TRAP-0116, SDC-TRAP-0119, SDC-TRAP-0120, SDC-TRAP-0121, SDC-TRAP-0128, SDC-TRAP-0129, SDC-TRAP-0131, SDC-TRAP-0149, SDC-TRAP-0152, SDC-TRAP-0168, SDC-TRAP-0173, SDC-TRAP-0174, SDC-TRAP-0175, SDC-TRAP-0176, SDC-TRAP-0177, SDC-TRAP-0178, SDC-TRAP-0194, SDC-TRAP-0195, and SDC-TRAP-0196. 
     
     
         13 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises vorinostat or a fragment or analog thereof. 
     
     
         14 . The SDC-TRAP of  claim 13 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0117 and SDC-TRAP-0118. 
     
     
         15 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises 5-Fluorouracil (5-FU) or a fragment or analog thereof. 
     
     
         16 . The SDC-TRAP of  claim 15 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0051, SDC-TRAP-0048, SDC-TRAP-0050, SDC-TRAP-0009, SDC-TRAP-0025, SDC-TRAP-0013, and SDC-TRAP-0137. 
     
     
         17 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises abiraterone or a fragment or analog thereof. 
     
     
         18 . The SDC-TRAP of  claim 17 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0150, SDC-TRAP-0151, and SDC-TRAP-0153. 
     
     
         19 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises bendamustine or a fragment or analog thereof. 
     
     
         20 . The SDC-TRAP of  claim 19 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0211, SDC-TRAP-0039, SDC-TRAP-0040, and SDC-TRAP-0069. 
     
     
         21 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises crizotinib or a fragment or analog thereof. 
     
     
         22 . The SDC-TRAP of  claim 21 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0134, SDC-TRAP-0139, and SDC-TRAP-0138. 
     
     
         23 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises doxorubicin or a fragment or analog thereof. 
     
     
         24 . The SDC-TRAP of  claim 23 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0198, SDC-TRAP-0199, and SDC-TRAP-0219. 
     
     
         25 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises a pemetrexed fragment. 
     
     
         26 . The SDC-TRAP of  claim 25 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0019, SDC-TRAP-0020, SDC-TRAP-0068, SDC-TRAP-0078, SDC-TRAP-0082, SDC-TRAP-0093, SDC-TRAP-0102, SDC-TRAP-0103, and SDC-TRAP-0130. 
     
     
         27 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises a fulvestrant or a fragment or analog thereof. 
     
     
         28 . The SDC-TRAP of  claim 27 , wherein the SDC-TRAP is SDC-TRAP-0148. 
     
     
         29 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises a topotecan or a fragment or analog thereof. 
     
     
         30 . The SDC-TRAP of  claim 29 , wherein the SDC-TRAP is SDC-TRAP-0159. 
     
     
         31 . The SDC-TRAP of  claim 2 , wherein the effector moiety comprises a Vascular Disrupting Agent (VDA) or a fragment or analog thereof. 
     
     
         32 . The SDC-TRAP of  claim 31 , wherein the SDC-TRAP is selected from the group consisting of SDC-TRAP-0098, SDC-TRAP-0099, SDC-TRAP-0158, SDC-TRAP-0085, and SDC-TRAP-0025. 
     
     
         33 . A pharmaceutical composition comprising a therapeutically effective amount of at least one SDC-TRAP of  claim 1  or a salt thereof, and at least one pharmaceutical excipient. 
     
     
         34 . A method of treating tumor in a subject in need thereof comprising administering the pharmaceutical composition of  claim 33  to the subject, thereby treating the subject. 
     
     
         35 . The method of  claim 34 , wherein the tumor volume is reduced. 
     
     
         36 . The method of  claim 35 , wherein the tumor is colorectal cancer, breast cancer, small cell lung cancer, sarcoma, or pancreatice cancer.

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