Modified cytotoxins and their therapeutic use

Abstract

The present disclosure generally provides compounds useful for treating cancer. In some aspects, the disclosure provides small-molecule cytotoxins that are chemically modified to include one or more moieties that include hydrophobic portions. In some embodiments, the disclosure provides small-molecule cytotoxins that are chemically modified with fatty acid-containing moieties. In some aspects, the disclosure provides compositions, such as pharmaceutical compositions, that include such modified small-molecule cytotoxins and a protein. In some embodiments, the protein is albumin or an albumin mimetic. Further, the disclosure provides various uses of these compounds and compositions.

1 - 40 . (canceled) 
     
     
         41 . A compound of formula (I)
   A 1 -X 1 —X 2 -A 2   (I)
   
       wherein:
 A 1  is a carboxylic acid group, a carboxylate anion group, or a carboxylate ester group of the formula —COOR a , wherein R a  is an alkyl group or an alkoxylate group; 
 A 2  is a cytotoxic drug moiety, which has a molecular weight of no more than 1600 Da; 
 X 1  is C 12-22  alkylene or C 12-22  alkenylene; and 
 X 2  is a direct bond, or an organic group that comprises one or more moieties selected from the group consisting of: —C(═O)—, —O—C(═O)—, —NH—C(═O)—, one or more units formed from a alkylene glycols, one or more units formed from alkanol amines, and one or more units formed from amino acids; 
 wherein when —X 2 —X 1 -A 1  connects to an oxygen atom or an NH group on the cytotoxic drug moiety, then —X 2 —X 1 -A 1  is selected from the group consisting of: —C(═O)—(CH 2 ) n1 —C(═O)—OH; —C(═O)—(CH 2 ) n1 —C(═O)—OCH 3 ; —C(═O)—(C 1-6  alkylene)-C(═O)—O—(CH 2 ) n2 —C(═O)—OH; —C(═O)—(C 1-6  alkylene)-NH—C(═O)—(CH 2 ) n1 —C(═O)—OH; —C(═O)—(C1-6 alkylene)-C(═O)—[(CH 2 ) 2 —O—] n3 (CH 2 ) n2 —C(═O)—OH; and —C(═O)—NH—(CH 2 ) n2 —C(═O)—OH; wherein n1 is an integer 12 to 24, n2 is an integer from 13 to 25, and n3 is an integer from 1 to 25. 
 
     
     
         42 . The compound of  claim 41 , wherein A 1  is a carboxylic acid group. 
     
     
         43 . The compound of  claim 42 , wherein the cytotoxic drug moiety has a molecular weight of no more than 1500 Da. 
     
     
         44 . The compound of  claim 42 , wherein the cytotoxic drug moiety is an organic moiety. 
     
     
         45 . The compound of  claim 42 , wherein the cytotoxic drug moiety is a paclitaxel moiety, an etoposide moiety, a gemcitabine moiety, a cyclophosphamide moiety, a chlorambucil moiety, a doxorubicin moiety, a daunorubicin moiety, a 5-fluorouracil moiety, a dactinomycin moiety, an amifostine moiety, a fludarabine moiety, a topotecan moiety, an ifosfamide moiety, a vincristine moiety, a carboplatin moiety, a vinblastine moiety, an imatinib moiety, a lenalidomide moiety, a pemetrexed moiety, an abiraterone moiety, an erlotinib moiety, a bortezomib moiety, an oxaliplatin moiety, a methotrexate moiety, a carfilzomib moiety, a crizotinib moiety, a vismodegib moiety, a ponatinib moiety, a tivozanib moiety, a carbozantinib moiety, an epirubicin moiety, a docetaxel moiety, a cisplatin moiety, an eribulun moiety, an ixabepilone moiety, a vinorelbine moiety, an everolimus moiety, a mytomycin C moiety, a sunitinib moiety, an irinotecan moiety, a leicovorim moiety, a tretinoin moiety, an allopurinol moiety, an asparaginase moiety, a bendamustine moiety, a bleomycin moiety, a folinic acid moiety, a capecitabine moiety, a cytarabine moiety, a dacarbazine moiety, a filgrastim moiety, a hydroxycarbamide moiety, a mercaptopurine moiety, a mesna moiety, a procarbazine moiety, a thioguanine moiety, and pharmaceutically acceptable salts of any of the foregoing. 
     
     
         46 . The compound of  claim 46 , wherein the drug moiety is selected from the group consisting of a paclitaxel moiety, a methotrexate moiety, a 5-fluorouracil moiety, a gemcitabine moiety, a pemetrexed moiety, and pharmaceutically acceptable salts of any of the foregoing. 
     
     
         47 . The compound of  claim 47 , wherein the drug moiety is a paclitaxel moiety. 
     
     
         48 . The compound of  claim 48 , wherein the paclitaxel moiety is a moiety of the formula: 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 42 , wherein X 1  is —(CH 2 ) 16 —. 
     
     
         50 . The compound of  claim 50 , wherein X 2  is —C(═O)—. 
     
     
         51 . A pharmaceutical composition comprising:
 a first compound, which is a compound of  claim 42 ; and   a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 50% equivalent to that of human serum albumin.   
     
     
         52 . The pharmaceutical composition of  claim 52 , wherein the protein is human serum albumin. 
     
     
         53 . The pharmaceutical composition of  claim 52 , further comprising a carrier. 
     
     
         54 . The pharmaceutical composition of  claim 54 , wherein the carrier comprises water. 
     
     
         55 . The pharmaceutical composition of  claim 55 , wherein the compound and the protein are non-covalently associated with each other with a binding constant (K b ) of at least 10 2  M −1 . 
     
     
         56 . The pharmaceutical composition of  claim 55 , wherein the compound and the protein are solvated by the carrier. 
     
     
         57 . The pharmaceutical composition of  claim 54 , which contains one or more first compounds and one or more proteins, wherein at least 90% by weight of the compounds in the composition are bound to proteins with a binding constant (K b ) of at least 10 2  M −1 . 
     
     
         58 . The pharmaceutical composition of  claim 58 , wherein at least at least 90% by weight of the protein-bound particles in the composition have a radius no greater than 5 nm, as measured by dynamic light scattering. 
     
     
         59 . A method of treating cancer, comprising:
 administering to a subject a composition of  claim 52 .