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 pharmaceutical composition comprising:
 (a) a first compound, which is 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, or a carboxylate ester of the formula —COOR a , wherein R a  is an alkyl or an alkoxylate group; 
 A 2  is a cytotoxic drug moiety, which has a molecular weight of no more than 1600 Da, wherein the cytotoxic drug moiety comprises an oxygen atom or an NH group through which it connects to —X 2 —X 1 -A 1 ; 
 X 1  is C 12-22  hydrocarbylene, wherein A 1  is separated from X 2  by at least 6 carbon atoms; and 
 X 2  is an organic group, wherein the organic group 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 alkylene glycols, one or more units formed from alkanol amines, one or more units formed from amino acids, one or more units formed from hydroxyl acids, and combinations thereof, and wherein the organic group comprises from 1 to 100 carbon atoms; and 
 (b) a protein, wherein the protein is human serum albumin or a protein whose sequence is at least 80% equivalent to that of human serum albumin. 
 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein the protein is human serum albumin. 
     
     
         43 . The pharmaceutical composition of  claim 41 , further comprising a carrier. 
     
     
         44 . The pharmaceutical composition of  claim 43 , wherein the carrier comprises water. 
     
     
         45 . The pharmaceutical composition of  claim 44 , 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 . 
     
     
         46 . The pharmaceutical composition of  claim 43 , wherein the compound and the protein are solvated by the carrier. 
     
     
         47 . The pharmaceutical composition of  claim 43 , 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 . 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein 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. 
     
     
         49 . A method of treating cancer, comprising:
 administering to a subject a composition of  claim 41 .