Conjugated small molecules
Provided herein are linker compounds and conjugates that include the linker compounds. In one embodiment, the linker compounds comprise 2 or 3 residues of 6-aminohexanoic acid and optionally 7-10 residues of polyethyleneglycol (PEG). The linker compounds are useful in forming conjugates with one or more components useful in biopharmaceutical or bioanalytical applications. In particular, the biopharmaceutically useful compounds are kinase inhibitors. The conjugates described herein have utility in a variety of diagnostic, separation, and therapeutic applications.
1 . A compound comprising the structure:
A-(X 1 —(CR 1 R 2 ) p -C(═X 2 )) n -X 3 -T 1 -(CR 3 R 4 X 4 CR 5 R 6 ) m -T 2 -L-B
wherein A and B are independently selected functional groups capable of forming a covalent linkage or a component useful in biopharmaceutical or bioanalytical applications;
X 1 , X 2 , X 3 , and X 4 are independently selected from the group consisting of O, S, and NH;
R 1 , R 2 , R 3 , R 4, R 5 , R 6, R 7 , and R 8 , are independently selected from the group consisting of hydrogen, halogen, or lower alkyl;
T 1 and T 2 are independently selected from the group consisting of (CH 2 ) r , a bond or triazole;
L is a bond or a moiety comprising a —NH— group;
p is 1, 2, 4, 4, 5, or 6;
n is 0, 1, 2, 3, 4, 5, or 6;
r is 1, 2, 3, 4, 5, or 6; and
m is equal to or greater than 3.
2 . The compound of claim 1 , wherein A and B are independently selected from the group consisting of a carboxylic acid group, an amine group, an aminoxy group, a hydrazide group, a semicarbazide group, a hydroxyl group, a thiol group, an isocyanate group, a thioisocyanate group, a maleimide group, a halide, azide, a boronic acid derivative and a carboxylic acid derivative.
3 . The compound of claim 1 , wherein A is biotin, a biotinyl group or a derivative of a biotinyl group.
4 . The compound of claim 1 , wherein X 4 is O.
5 . The compound of claim 1 , wherein X 2 is O.
6 . The compound of claim 1 , wherein R 1 , R 2 , R 3 , R 4 , R 5 , and R 6 are hydrogen.
7 . The compound of claim 1 , wherein p is 5; n is 1, 2, or 3; and m is 6, 7, 8, 9, or 10.
8 . The compound of claim 1 , wherein T 2 is CH 2 .
9 . The compound of claim 1 , wherein T 1 is CH 2 .
10 . The compound of claim 1 , wherein T 1 is a triazole.
11 . The compound of claim 1 , wherein L is a direct bond.
12 . The compound of claim 1 , wherein L is a moiety comprising an —NH— group.
13 . The compound of claim 12 , wherein L is a moiety comprising an —NH—C(O)— group.
14 . The compound of claim 12 , wherein L is selected from the group consisting of —NH—, —C(O)NH—, —NHC(O)NH—, and —C(O)CH 2 CH 2 C(O)NH—.
15 . The compound of claim 1 , wherein A is a component useful in biopharmaceutical or bioanalytical applications.
16 . The compound of claim 15 , wherein B is a component useful in biopharmaceutical or bioanalytical applications.
17 . The compound of claim 16 , wherein at least one of A or B is a binding agent, a label compound, or a therapeutic agent.
18 . The compound of claim 17 , wherein A or B is a binding agent selected from the group consisting of biotin, antigen, antibody, riboflavin, cytostatin, and val-phosphate.
19 . The compound of claim 17 , wherein A or B is a therapeutic agent selected from the group consisting of spiramycin, ipriflavone, mesalazine, and crotamiton.
20 . The compound of claim 17 , wherein A or B is a label compound selected from the group consisting of a fluorescent label, an enzyme, an enzyme substrate, and a radioactive label.
21 . The compound of claim 20 , wherein A or B is a fluorescent label selected from fluorescein, rhodamine, FITC (fluorescein isothiocyanate), HEX (4,5,2′,4′,5′,7′-hexachloro-6-carboxyfluorescein), 5-IAF, TAMRA (6-carboxytetramethylrhodamine), TET (4,7,2′,7′-tetrachloro-6-carboxyfluorescein), XRITC (rhodamine-X-isothiocyanate), texas red, CY2, CY3 and CY5.
22 . The compound of claim 20 , wherein one of A or B is an enzyme selected from alkaline phosphatase, horseradish peroxidase, β-galactosidase and luciferase.
23 . The compound of claim 16 , wherein at least one of A or B is a kinase inhibitor.
24 . The compound of claim 16 , wherein at least one of A or B is a binding agent or a label compound and the other of A or B is a therapeutic agent.
25 . The compound of claim 24 , wherein the therapeutic agent is a kinase inhibitor.
26 . The compound of claim 25 , wherein the kinase inhibitor is selected from the group consisting of:
27 . A compound selected from the group consisting of compound 27, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, and 74.
28 . A compound having the structure:
wherein n is 0, 1, or 2, LC is (CH 2 ) 5 C(O)NH, and PEG is (CH 2 CH 2 O).