Compounds for treating cancer
The present invention provides compounds, compositions thereof, and methods of using the same.
1. A method for treating cancer in a patient in need thereof, comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Bicycle is a polypeptide which is covalently bound to a molecular scaffold such that two or more peptide loops are subtended between attachment points to the scaffold, wherein the polypeptide is:
C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C- (SEQ ID NO: 1) wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V; or
C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5) wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine;
Spacer is
AA 1 -AA 2 is a bivalent moiety comprising at least one citrulline moiety that connects the Spacer moiety with the Linker moiety, wherein each of AA 1 and AA 2 is an independently selected natural or unnatural amino acid moiety;
Linker is a bivalent spacer moiety that connects AA 1 -AA 2 moiety with the Toxin moiety; and
Toxin is a chemotherapeutic agent.
2. The method of claim 1 , wherein the cancer is MT1-positive cancer.
3. The method of claim 1 , wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasalpharyngeal/laryngeal/oesophageal cancer, ovarian cancer, epithelial cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothlioma, bladder cancer, hepatocellular carcinoma, and prostate cancer.
4. The method of claim 1 , wherein the polypeptide is -C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C-(SEQ ID NO: 1), wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V.
5. The method of claim 1 , wherein the polypeptide is -C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5), wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine.
6. The method of claim 1 , wherein the molecular scaffold is
7. The method of claim 1 , wherein the Bicycle is of formula II′:
wherein:
each of L 1 , L 2 , and L 3 is independently a C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —S—, —N(R)—, —C(O)—, —C(O)N(R)—, or —N(R)C(O)—;
each R is independently hydrogen or C 1-4 alkyl;
Ring A is a 6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
comprises a polypeptide targeting MT1-MMP, wherein the polypeptide is of SEQ ID NO: 1 or SEQ ID NO: 5; and
indicates the site of attachment to the Spacer.
8. The method of claim 7 , wherein each of L 1 , L 2 , and L 3 is —CH 2 —, or each of L 1 , L 2 , and L 3 is —C(O)CH 2 CH 2 —.
9. The method of claim 7 , wherein Ring A is selected from:
10. The method of claim 7 , wherein the Bicycle is:
11. The method of claim 1 , wherein the AA 1 -AA 2 moiety is
12. The method of claim 1 , wherein the Linker moiety is
13. The method of claim 1 , wherein the Toxin is selected from the group consisting of MMAE, MMAF, DM1, DM4, SN38, doxorubicin and a duocarmycin analog.
14. The method of claim 1 , wherein said compound is
or a pharmaceutically acceptable salt thereof.
15. A method for treating cancer in a patient in need thereof, comprising administering to said patient a compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
Bicycle is a polypeptide which is covalently bound to a molecular scaffold such that two or more peptide loops are subtended between attachment points to the scaffold;
Spacer is a bivalent moiety that connects the Bicycle moiety with the AA 1 -AA 2 moiety, which is selected from
AA 1 -AA 2 is a bivalent moiety comprising at least one citrulline moiety that connects the Spacer moiety with the Linker moiety, wherein each of AA 1 and AA 2 is an independently selected natural or unnatural amino acid moiety;
Linker is a bivalent spacer moiety that connects AA 1 -AA 2 moiety with the Toxin moiety; and
Toxin is a chemotherapeutic agent.
16. The method of claim 15 , wherein the polypeptide is -C-X-U/O-X-X-G-C-E-D-F-Y-X-X-C-(SEQ ID NO: 1) wherein X represents any amino acid residue; U represents a polar, uncharged amino acid residue selected from N, C, Q, M, S and T; and O represents a non-polar aliphatic amino acid residue selected from G, A, I, L, P and V.
17. The method of claim 15 , wherein the polypeptide is -C(D-Ala)NE(1Nal)(D-Ala)CEDFYD(tBuGly)C- (SEQ ID NO: 5), wherein D-Ala represents D-alanine; 1Nal represents 1-naphthylalanine; and tBuGly represents tert-butylglycine.
18. The method of claim 15 , wherein the molecular scaffold is
19. The method of claim 15 , wherein the Bicycle is of formula II′:
wherein:
each of L 1 , L 2 , and L 3 is independently a C 1-6 bivalent straight or branched saturated or unsaturated hydrocarbon chain wherein 1-2 methylene units of the chain are independently and optionally replaced with —S—, —N(R)—, —C(O)—, —C(O)N(R)—, or —N(R)C(O)—;
each R is independently hydrogen or C 1-4 alkyl;
Ring A is a 6-membered saturated, partially unsaturated, or aromatic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
comprises a polypeptide targeting MT1-MMP; and
indicates the site of attachment to the Spacer.
20. The method of claim 19 , wherein each of L 1 , L 2 , and L 3 is —CH 2 —, or each of L 1 , L 2 , and L 3 is —C(O)CH 2 CH 2 —.
21. The method of claim 19 , wherein Ring A is selected from:
22. The method of claim 19 , wherein the Bicycle is:
23. The method of claim 15 , wherein the AA 1 -AA 2 moiety is
24. The method of claim 15 , wherein the Linker moiety is
25. The method of claim 15 , wherein the Toxin is selected from the group consisting of MMAE, MMAF, DM1, DM4, SN38, doxorubicin and a duocarmycin analog.
26. The method of claim 15 , wherein the cancer is MT1-positive cancer.
27. The method of claim 15 , wherein the cancer is selected from colorectal cancer, non-small cell lung cancer, breast cancer, gastric cancer, sarcoma, myeloma, nasalpharyngeal/laryngeal/oesophageal cancer, ovarian cancer, epithelial cancer, melanoma, glioma, astrocytoma, glioblastoma, neuroblastoma, mesothlioma, bladder cancer, hepatocellular carcinoma, and prostate cancer.
28. The method of claim 15 , wherein said compound is selected from:
or a pharmaceutically acceptable salt thereof.