US2021085700A1PendingUtilityA1

Targeted therapeutics

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Assignee: MADRIGAL PHARMACEUTICALS INCPriority: Sep 10, 2013Filed: Sep 23, 2020Published: Mar 25, 2021
Est. expirySep 10, 2033(~7.2 yrs left)· nominal 20-yr term from priority
Inventors:Dinesh U. ChimmanamadaWeiwen YingJunyi ZhangTeresa Kowalczyk-PrzewlokaJun JiangSami OsmanGenliang LuDharma VutukuriJames LochShoujun Chen
A61K 31/454A61K 31/4545A61K 31/565A61K 31/519A61K 38/05A61K 31/416A61K 31/497A61K 31/4188A61K 31/506A61K 31/513A61K 31/4184A61K 31/167A61K 31/495A61K 31/704A61K 47/545A61K 31/4745A61K 31/42A61K 31/58A61K 31/165A61P 35/00
57
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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 is an Hsp90 ligand or prodrug thereof. 
     
     
         2 . The SDC-TRAP of  claim 1 , wherein the Hsp90 ligand is an Hsp90 inhibitor. 
     
     
         3 . The SDC-TRAP of  claim 2 , wherein the Hsp90 inhibitor is selected from the group consisting of geldanamycins, macbecins, tripterins, tanespimycins, radicicols, AUY-922, VER-82160, AT-13387, Geldanamycin, SNX-5422, BI113028, and MPC-3100. 
     
     
         4 . The SDC-TRAP of  claim 1 , wherein the effector moiety is a therapeutic moiety. 
     
     
         5 . The SDC-TRAP of  claim 4 , wherein the therapeutic moiety is a cytotoxic moiety. 
     
     
         6 . The SDC-TRAP of  claim 5 , wherein the cytotoxic moiety is dasatinib, SN-38, bendamustine, a VDA, doxorubicin, pemetrexed, vorinostat, lenalidomide, irinotecan, ganetespib, docetaxel, 17-AAG, 5-FU, abiraterone, crizotinib, KW-2189, BUMB2, DC1, CC-1065, adozelesin, or fragment thereof. 
     
     
         7 . 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. 
     
     
         8 . The SDC-TRAP of  claim 1 , wherein the binding moiety and the effector moiety are covalently attached by a linker. 
     
     
         9 . The SDC-TRAP of  claim 8 , wherein the linker comprises a cleavable linker. 
     
     
         10 . The SDC-TRAP of  claim 9 , wherein the cleavable linker comprises an enzymatically cleavable linker. 
     
     
         11 . The SDC-TRAP of  claim 8 , wherein the linker is selected from the group consisting of disulfide, carbamate, amide, ester, and ether linkers. 
     
     
         12 . The SDC-TRAP of  claim 1 , wherein the SDC-TRAP is SDC-TRAP-0236, SDC-TRAP-0237, SDC-TRAP-0238, SDC-TRAP-0239, SDC-TRAP-0240, SDC-TRAP-0241, SDC-TRAP-0242, SDC-TRAP-0243, SDC-TRAP-0244, SDC-TRAP-0245, SDC-TRAP-0246, SDC-TRAP-0247, SDC-TRAP-0248, SDC-TRAP-0249, SDC-TRAP-0250, SDC-TRAP-0251, SDC-TRAP-0252, SDC-TRAP-0253, SDC-TRAP-0254, SDC-TRAP-0255, SDC-TRAP-0256, SDC-TRAP-0257, SDC-TRAP-0258, SDC-TRAP-0259, SDC-TRAP-0260, SDC-TRAP-0261, SDC-TRAP-0262, SDC-TRAP-0263, SDC-TRAP-0264, SDC-TRAP-0265, SDC-TRAP-0266, SDC-TRAP-0267, SDC-TRAP-0268, SDC-TRAP-0269, SDC-TRAP-0270, SDC-TRAP-0271, SDC-TRAP-0272, SDC-TRAP-0273, SDC-TRAP-0274, SDC-TRAP-0275, SDC-TRAP-0276, SDC-TRAP-0277, SDC-TRAP-0278, SDC-TRAP-0279, SDC-TRAP-0280, SDC-TRAP-0281, SDC-TRAP-0282, SDC-TRAP-0283, SDC-TRAP-0284, SDC-TRAP-0285, SDC-TRAP-0286, SDC-TRAP-0287, SDC-TRAP-0288, SDC-TRAP-0289, SDC-TRAP-0290, SDC-TRAP-0291, SDC-TRAP-0292, SDC-TRAP-0293, SDC-TRAP-0294, SDC-TRAP-0295, SDC-TRAP-0296, SDC-TRAP-0297, SDC-TRAP-0298, SDC-TRAP-0299, SDC-TRAP-0300, SDC-TRAP-0301, SDC-TRAP-0302, SDC-TRAP-0303, SDC-TRAP-0304, SDC-TRAP-0305, SDC-TRAP-0306, SDC-TRAP-0307, SDC-TRAP-0308, SDC-TRAP-0309, SDC-TRAP-0310, SDC-TRAP-0311, SDC-TRAP-0312, SDC-TRAP-0313, SDC-TRAP-0314, SDC-TRAP-0315, SDC-TRAP-0316, SDC-TRAP-0317, SDC-TRAP-0318, SDC-TRAP-0319, SDC-TRAP-0320, SDC-TRAP-0321, SDC-TRAP-0322, SDC-TRAP-0323, SDC-TRAP-0324, SDC-TRAP-0325, SDC-TRAP-0326, SDC-TRAP-0327, SDC-TRAP-0328, SDC-TRAP-0329, SDC-TRAP-0330, SDC-TRAP-0331, SDC-TRAP-0332, SDC-TRAP-0333, SDC-TRAP-0334, SDC-TRAP-0335, SDC-TRAP-0336, SDC-TRAP-0337, SDC-TRAP-0338, SDC-TRAP-0339, SDC-TRAP-0340, SDC-TRAP-0341, SDC-TRAP-0342, SDC-TRAP-0343, SDC-TRAP-0344, SDC-TRAP-0345, SDC-TRAP-0346, SDC-TRAP-0347, SDC-TRAP-0348, SDC-TRAP-0349, SDC-TRAP-0350, SDC-TRAP-0351, SDC-TRAP-0352, SDC-TRAP-0353, SDC-TRAP-0354, SDC-TRAP-0355, SDC-TRAP-0356, SDC-TRAP-0357, SDC-TRAP-0358, SDC-TRAP-0359, SDC-TRAP-0360, SDC-TRAP-0361, SDC-TRAP-0362, SDC-TRAP-0363, SDC-TRAP-0364, SDC-TRAP-0365, SDC-TRAP-0366, SDC-TRAP-0367, SDC-TRAP-0368, SDC-TRAP-0369, SDC-TRAP-0370, SDC-TRAP-0371, SDC-TRAP-0372, SDC-TRAP-0373, SDC-TRAP-0374, SDC-TRAP-0375, SDC-TRAP-0376, SDC-TRAP-0377, SDC-TRAP-0378, SDC-TRAP-0379, SDC-TRAP-0380, SDC-TRAP-0381, SDC-TRAP-0382, SDC-TRAP-0383, SDC-TRAP-0384, SDC-TRAP-0385, SDC-TRAP-0386, SDC-TRAP-0387, SDC-TRAP-0388, SDC-TRAP-0389, SDC-TRAP-0390, SDC-TRAP-0391, SDC-TRAP-0392, SDC-TRAP-0393, SDC-TRAP-0394, SDC-TRAP-0395, SDC-TRAP-0396, SDC-TRAP-0397, SDC-TRAP-0398, SDC-TRAP-0399, SDC-TRAP-0400, SDC-TRAP-0401, SDC-TRAP-0402, SDC-TRAP-0403, SDC-TRAP-0404, SDC-TRAP-0405, SDC-TRAP-0406, SDC-TRAP-0407, SDC-TRAP-0408, SDC-TRAP-0409, SDC-TRAP-0410, SDC-TRAP-0411, SDC-TRAP-0412, SDC-TRAP-0413, SDC-TRAP-0422, SDC-TRAP-0423, SDC-TRAP-0424, SDC-TRAP-0425, SDC-TRAP-0426, SDC-TRAP-0427, SDC-TRAP-0428, SDC-TRAP-0430, SDC-TRAP-0431, SDC-TRAP-0432, SDC-TRAP-0433, SDC-TRAP-0434, SDC-TRAP-0435, SDC-TRAP-0436, SDC-TRAP-0437, SDC-TRAP-0438, or SDC-TRAP-0440. 
     
     
         13 . The SDC-TRAP of  claim 1 , wherein the SDC-TRAP is able to enter a cell by passive diffusion or by active transport. 
     
     
         14 . The SDC-TRAP of  claim 1 , wherein the binding moiety has a molecular weight of less than 800 Daltons or wherein the effector moiety has a molecular weight of less than 800 Daltons. 
     
     
         15 . The SDC-TRAP of  claim 1 , wherein the Hsp90 binding moiety and the effector moiety are approximately equal in size. 
     
     
         16 . The SDC-TRAP of  claim 1 , wherein the Hsp90 binding moiety interacts with the N-terminal domain of Hsp90, C-terminal domain of Hsp90, or the middle domain of Hsp90. 
     
     
         17 . The SDC-TRAP of  claim 1 , wherein the Hsp90 binding moiety has a K d  of 100 nM or higher. 
     
     
         18 . The SDC-TRAP of  claim 1 , wherein when administered to a subject the SDC-TRAP present at a ratio of at least 2:1 in tumor cells compared to plasma. 
     
     
         19 . The SDC-TRAP of  claim 1 , wherein the SDC-TRAP is present in cancer cells for at least 24 hours. 
     
     
         20 . The SDC-TRAP of  claim 1 , wherein the effector moiety is released for a period of at least 6 hours. 
     
     
         21 . The SDC-TRAP of  claim 1 , wherein the effector moiety is selectively released inside a cancer cell. 
     
     
         22 . The SDC-TRAP of  claim 1 , wherein the Hsp90 binding moiety is an Hsp90 inhibitor that is ineffective as a therapeutic agent when administered alone. 
     
     
         23 . A pharmaceutical composition comprising a therapeutically effective amount of at least one SDC-TRAP of  claim 1 , and at least one pharmaceutical excipient. 
     
     
         24 . A method for treating a subject in need thereof comprising administering a therapeutically effective amount of at least one SDC-TRAP of  claim 1  to the subject, thereby treating the subject. 
     
     
         25 . The method of  claim 24 , wherein the subject has a cancer. 
     
     
         26 . The method of  claim 24 , wherein the subject has a colon cancer, a breast cancer, an ovarian cancer, a lung cancer, or a skin cancer. 
     
     
         27 . The method of  claim 26 , wherein the lung cancer comprises small cell lung cancer. 
     
     
         28 . The method of  claim 24 , wherein the subject has chronic bronchitis, asthma, or actinic keratosis.

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