Compounds having RD targeting motifs and methods of use thereof
The present invention provides compounds that have motifs that target the compounds to cells that express integrins. In particular, the compounds have peptides with one or more RD motifs conjugated to an agent selected from an imaging agent and a targeting agent. The compounds may be used to detect, monitor and treat a variety of disorders mediated by integrins.
1. A compound having the formula:
R 1 —[X 1 m —R-D-X 2 p ] n —Y—R 2
wherein:
R 1 is a carbocyanine dye selected from Cypate (cypate 4), LS288, LS798, LS276, LS843, Cypate 3, and Cypate 2;
R 2 is selected from a treatment agent, hydrogen, hydroxyl, NH 2 , hydrocarbyl, and substituted hydrocarbyl; wherein the treatment agent selected from daunorubicin, adriamycin, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, cytosine arabinoside, methotrexate, aminopterin, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine, mechlorethamine, melphalan, temozolomide, carmustine, lomustine, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide, teniposide, cytotoxins, macromycin, taxol, cholchicine, VEGF inhibitors, and anti-VEGF antibodies;
[X 1 m —R-D-X 2 p ] n —Y together form a linear or cyclic peptide selected from the group consisting of
SEQ
ID
NO:
[X 1 m -R-D-X 2 p ] n Y
8
[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Lys-Tyr
9
[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr
10
[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr-Lys
11
[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr
12
[Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr
17
Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr
18
Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr
19
Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr-Lys
20
Gly-[Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr-Lys
21
Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr
22
Gly-[Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr
23
Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]- D Tyr
and
a dash (-) represent a covalent bond.
2. The compound of claim 1 , further comprising a polyethylene glycol moiety conjugated to the carbocyanine dye.
3. The compound of claim 1 , wherein the Y is radiolabeled.
4. The compound of claim 3 , wherein the radiolabel is fluorine or iodine radionuclide.
5. The compound of claim 1 , further comprising a linker, L 1 , that conjugates R 1 to X 1 and a linker, L 2 , that conjugates R 2 to Y.
6. The compound of claim 5 , wherein the linker is selected from an amino acid residue, a hydrocarbyl and a substituted hydrocarbyl.
7. A compound having formula (II):
wherein:
R 3 is selected from daunorubicin, adriamycin, paclitaxel, docetaxel, vinblastine, vincristine, vinorelbine, 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, pemetrexed, cytosine arabinoside, methotrexate, aminopterin, busulfan, cisplatin, carboplatin, chlorambucil, cyclophosphamide, ifosfamide, dacarbazine, mechlorethamine, melphalan, temozolomide, carmustine, lomustine, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, topotecan, irinotecan, etoposide, teniposide, cytotoxins, macromycin, taxol, cholchicine, VEGF inhibitors, and anti-VEGF antibodies; and
R 4 is selected from the group consisting of:
SEQ
ID
NO:
R 4
8
CONH-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Lys-Tyr-OH
9
CONH-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr-OH
10
CONH-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr-Lys-OH
11
CONH-[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr-OH
12
CONH-[Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr-OH
13
CONH-[Cys-Arg-Gly-Asp-Ser-Pro-Cys]-Tyr-OH
14
CONH-[ D Cys-Arg-Gly-Asp-Ser-Pro-Cys]-Tyr-OH
15
CONH-[ D Cys-Arg-Gly-Asp-Ser-Pro- D Cys]-Tyr-OH
17
CONH-Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]-Tyr-
OH
18
CONH-Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr-
OH
19
CONH-Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr-
Lys-OH
20
CONH-Gly-[Cys-Gly-Arg-Asp-Ser-Pro-Cys]- D Tyr-
Lys-OH
21
CONH-Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr-
OH
22
CONH-Gly-[Cys-Gly-Arg-Asp-Ser-Pro- D Cys]-Tyr-
OH
23
CONH-Gly-[ D Cys-Gly-Arg-Asp-Ser-Pro- D Cys]- D Tyr-
OH.
8. The compound of claim 7 , wherein R 4 is selected from SEQ ID NOS 18, 19, 20, 21, and 23.
9. The compound of claim 7 , wherein one or more amino acid residues are inserted prior to or after the Tyr of R 4 .
10. The compound of claim 9 , wherein a Lys is inserted after the Tyr.
11. The compound of claim 7 , wherein the Tyr is halogenated.
12. The compound of claim 11 , wherein the halogen is a radioisotope selected from 18 F, 75 Br, 77 Br, 122 I, 123 I, 124 I, 125 I, 129 I, 131 I, and 211 At.
13. The compound of claim 1 , wherein [X 1 m —R-D-X 2 p ] n —Y is SEQ ID NO: 9.
14. The compound of claim 1 , wherein [X 1 m —R-D-X 2 p ] n —Y is SEQ ID NO: 11.