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 compound of formula (I)
A 1 -X 1 —X 2 -A 2 (I)
wherein:
A 2 is a paclitaxel moiety; and
—X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—H, wherein n1 is an integer from 12 to 24; or — 2 —X 1 -A 1 is C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.
2. The compound of claim 1 wherein the paclitaxel moiety is a moiety of the formula:
3. The compound of claim 1 , which is a compound of the formula:
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising:
a compound of claim 1 ; 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.
5. The pharmaceutical composition of claim 4 , wherein the protein is human serum albumin.
6. The pharmaceutical composition of claim 4 , further comprising a carrier.
7. The pharmaceutical composition of claim 6 , wherein the carrier comprises water.
8. A method of treating cancer, comprising:
administering to a subject a composition of claim 4 .
9. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) n1 —C(═O)—OH, wherein n1is an integer from 12 to 24.
10. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 14 —C(═O)—OH.
11. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 16 —C(═O)—OH.
12. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 18 —C(═O)—OH.
13. The compound of claim 1 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.
14. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 14 —C(═O)—OH.
15. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 18 —C(═O)—OH.
16. The compound of claim 2 , wherein —X 2 —X 1 -A 1 is —C(═O)—(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —C(═O)—OH.
17. The compound of claim 1 , which is a compound of the formula:
18. A pharmaceutical composition comprising:
a compound of claim 3 ; 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.
19. A pharmaceutical composition comprising:
a compound of claim 17 ; 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.
20. A method of treating cancer, comprising:
administering to a subject a composition of claim 18 .
21. A method of treating cancer, comprising:
administering to a subject a composition of claim 19 .