Modified cytotoxins and their therapeutic use
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. A pharmaceutical composition comprising:
a first compound, which is a compound of formula (I)
A 1 -X 1 X— 2 -A 2 (I)
wherein:
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 ; and
—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; and —C(═O)—(C 1-6 alkylene)-C(═O)—O—[(CH 2 ) 2 —O-] n3 (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; and
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.
2. The pharmaceutical composition of claim 1 , wherein the protein is human serum albumin.
3. The pharmaceutical composition of claim 1 , further comprising a carrier.
4. The pharmaceutical composition of claim 3 , wherein the carrier comprises water.
5. The pharmaceutical composition of claim 4 , 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 .
6. The pharmaceutical composition of claim 3 , wherein the compound and the protein are solvated by the carrier.
7. The pharmaceutical composition of claim 3 , 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 .
8. The pharmaceutical composition of claim 7 , 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.
9. A method of treating cancer, comprising:
administering to a subject a composition of claim 1 .
10. The pharmaceutical composition of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—OH; —(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; or —(C═O)—(C 1-6 alkylene)-C(═O)—O—[(CH 2 ) 2 —O—] n3 —(CH 2 ) n2 —C(═O)—OH.
11. The pharmaceutical composition of claim 1 , wherein the cytotoxic drug moiety has a molecular weight of no more than 1500 Da.
12. The pharmaceutical composition of claim 1 , wherein the cytotoxic drug moiety is an organic moiety.
13. The pharmaceutical composition of claim 1 , wherein n1 or n2 is 16.