Programmable polymeric drugs
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): (I) or a stereoisomer, tautomer or salt thereof, wherein R1, R2, R3, L, L1, L2, L3, L4, M, m and n are as defined herein. Methods associated with preparation and use of such compounds is also provided.
1. A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently a biologically active moiety selected from an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, an alkylating agent and an anti-cancer drug, a fluorescent dye, an imaging agent, or a radioisotope binding site, provided at least one occurrence of M is not a fluorescent dye;
L is a physiologically cleavable linker comprising one of the following structures:
wherein:
R is H, methyl, ethyl, isopropyl, tert-butyl, or phenyl;
X is O or CH 2 ;
n′ is an integer greater than 0; and
L 1a and L 1b are optional linkers independently having one of the following structures:
L 1 , L 2 , L 3 and L 4 are, at each occurrence, independently an optional heteroalkylene linker, wherein at least one of L 1 and L 4 is present;
R 1 is, at each occurrence, independently a side chain of a natural or unnatural amino acid;
R 2 and R 3 are each independently —H, —OH, —SH, alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, Q or a protected form thereof, or L′, wherein the alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl and alkyloxycarbonyl are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether, or combinations thereof;
Q is, at each occurrence, independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q′ on a targeting moiety;
L′ is, at each occurrence, independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support or solid support residue, a linker comprising a covalent bond to a solid support or solid support residue or a linker comprising a covalent bond to a further compound of structure (I);
m is, at each occurrence, independently an integer of zero or greater; and
n is an integer of one or greater.
2. The compound of claim 1 , wherein R 1 is, at each occurrence, independently H, alkyl, —CH 2 CO 2 − , —CH 2 CH 2 CO 2 − , —CH 2 CH 2 CH 2 CH 2 NH 3 + , —CH 2 CH 2 CH 2 NHC(═NH 2 + )NH 2 or imidazolyl.
3. The compound of claim 1 , wherein R 1 , L 1 and m are selected such that
has an amino acid sequence of (G) 10 , (GDGDGDGDGD) or (GKGKGKGKGK).
4. The compound of claim 1 , wherein R 1 , L 1 and m are selected such that
has an amino acid sequence capable of forming an α-helix or β-sheet secondary structure.
5. The compound of claim 4 , wherein the amino acid sequence is (GGEEFMLVYKFARKHGG) or (GGMSMVVSGG).
6. The compound of claim 1 , wherein at least one occurrence of L 1 or L 4 , or both, has the following structure:
7. The compound of claim 1 , wherein at least one occurrence of L 1 or L 4 , or both, has the following structure:
8. The compound of claim 1 , wherein R 2 is —NH 2 .
9. The compound of claim 1 , wherein one of R 2 or R 3 is L′ and L′ is a linker comprising a covalent bond to a polymeric bead or non-polymeric bead.
10. The compound of claim 1 , wherein one of R 2 or R 3 is L′ and L′ is a targeting moiety or a heteroalkylene linker to a targeting moiety.
11. The compound of claim 1 , wherein the targeting moiety is an antibody or cell surface receptor antagonist.
12. The compound of claim 11 , wherein the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, or a MET inhibitor.
13. The compound of claim 1 , wherein L is, at each occurrence, independently a linker comprising an amide bond, an ester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano, a nitro or combinations thereof.
14. The compound of claim 1 , wherein M is, at each occurrence, independently selected from one of the following structures:
15. The compound of claim 1 , wherein M is, at each occurrence, independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen.
16. The compound of claim 15 , wherein the tumor cell antigen is an EGFR, a HER 2, a folate receptor, CD 20 or CD 33.
17. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
18. A composition comprising a plurality of conjugates, the conjugates comprising a compound of claim 1 covalently bound to an antibody via a single linkage, wherein the plurality of conjugates has at least 90% structural homogeneity.
19. The composition of claim 18 , wherein one of R 2 and R 3 is —OP(═R a )(R b ) OL′ or L′, and L′ is the antibody or a linker comprising a covalent bond to the antibody.
20. A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently a biologically active moiety selected from an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, an alkylating agent or an anti-cancer drug, a fluorescent dye, an imaging agent, or a radioisotope binding site, provided at least one occurrence of M is not a fluorescent dye;
L is a physiologically cleavable linker comprising one of the following structures:
wherein:
R is H, methyl, ethyl, isopropyl, tert-butyl, or phenyl;
X is O or CH 2 ;
n′ is an integer greater than 0; and
L 1a and L 1b are optional linkers independently having one of the following structures:
L 2 and L 4 are, at each occurrence, absent;
L 3 is, at each occurrence, independently a heteroalkylene linker;
R 2 and R 3 are each independently —H, —OH, —SH, alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, Q or a protected form thereof, or L′, wherein the alkyl, alkoxy, alkylether, heteroalkyl, alkylaminyl, alkylcarbonyl and alkyloxycarbonyl are optionally substituted with hydroxyl, amino, sulfhydryl, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether, or combinations thereof;
Q is, at each occurrence, independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q′ on a targeting moiety;
L′ is, at each occurrence, independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support or solid support residue, a linker comprising a covalent bond to a solid support or solid support residue or a linker comprising a covalent bond to a further compound of structure (I);
n is an integer of one or greater; and
R 1 , L 1 and m are selected such that
has an amino acid sequence of (G) 10 , (GDGDGDGDGD) or (GKGKGKGKGK).
21. The compound of claim 20 , having one of the following structures:
22. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein each M is independently a biologically active moiety effective for treating the disease.