Peptide-drug conjugates
Peptide-drug conjugates comprising p-aminobenzyl carbamoyl or p-aminobenzolyl carbonate self-immolating linkers are disclosed. The peptide-drug conjugates comprise a peptide moiety that can be cleaved by cellular proteases, bound to the self-immolating linker, which linker is bound to a cytotoxic drug moiety. Upon cleavage of the peptide moiety, the linker self-immolates, releasing the cytotoxic drug in active form. Dimeric structures of the peptide drug conjugates comprising two molecules of cytotoxic drug per conjugate are also disclosed.
1. A peptide-drug conjugate, which is
N α -succinamic acid-Ala-Ala-Asn-PABC-mitomycin;
or a pharmaceutically acceptable salt thereof,
wherein the mitomycin is bonded to PABC at a C-1″ aziridine nitrogen of the mitomycin; and PABC is a p-aminobenzyl carbamoyl linker moiety.
2. A pharmaceutical composition comprising at least one peptide-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically-acceptable carrier.
3. The pharmaceutical composition of claim 2 , packaged as one or more individual dosages.
4. A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a peptide-drug conjugate of claim 1 , or a pharmaceutically acceptable salt thereof.
5. A method of treating cancer in a mammal in need thereof, wherein the method comprises administering an anti-cancer effective amount of a pharmaceutical composition of claim 2 .
6. The method of claim 4 , wherein said cancer is a solid tumor.
7. The method of claim 4 , wherein said cancer is colon cancer, bladder cancer, breast cancer, cervical cancer, ovarian cancer, stomach cancer, pancreatic cancer, lung cancer, liver cancer, oesophageal cancer, bowel cancer, skin cancer, or prostate cancer.
8. The method of claim 4 , wherein said cancer is colon cancer.
9. The method of claim 4 , wherein said cancer is bladder cancer.
10. The method of claim 4 , wherein said cancer is breast cancer.
11. The method of claim 4 , wherein said cancer is cervical cancer.
12. The method of claim 4 , wherein said cancer is ovarian cancer.
13. The method of claim 4 , wherein said cancer is stomach cancer.
14. The method of claim 4 , wherein said cancer is pancreatic cancer.
15. The method of claim 4 , wherein said cancer is lung cancer.
16. The method of claim 4 , wherein said cancer is liver cancer.
17. The method of claim 4 , wherein said cancer is oesophageal cancer.
18. The method of claim 4 , wherein said cancer is bowel cancer.
19. The method of claim 4 , wherein said cancer is skin cancer.
20. The method of claim 4 , wherein said cancer is prostate cancer.