US2016375145A1PendingUtilityA1
Etoposide and doxorubicin conjugates for drug delivery
Est. expiryOct 15, 2028(~2.3 yrs left)· nominal 20-yr term from priority
A61P 35/00C07K 14/515A61K 31/704A61K 39/39558A61K 47/64A61K 38/10A61K 31/337A61K 31/04C07H 17/04A61K 31/7048A61K 45/06A61K 47/48246A61K 47/62
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Claims
Abstract
The invention relates to improvements in the field of drug delivery. More particularly, the invention relates to polypeptides having a hydrolyzable covalent bond to a therapeutic agent that includes, etoposide, etoposide 4′-dimethylglycine or doxorubicin. These polypeptide conjugates can be used as vectors to transport the podophyllotoxin derivative across the blood brain barrier (BBB) or into particular cell types such as ovary, liver, lung, or kidney. The invention also relates to pharmaceutical compositions that include the compounds of the invention and to uses thereof in methods of treatment.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound, or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence substantially identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:1-105 and 107-116, or a functional derivative thereof, wherein said amino acid sequence comprises a covalent bond from an amino acid of said amino acid sequence to a podophyllotoxin derivative, and wherein said podophyllotoxin derivative is a compound having a structure according to Formula (I)
or a stereoisomer or a pharmaceutically acceptable salt thereof, wherein
each R 1 , R 2 , and R 3 is selected, independently, from H, optionally substituted C 1-6 alkyl, C(O)R 8 , P(O)(OR 9 )(OR 10 ), S(O) 2 (OR 9 ), or a hydrolyzable linker Y that comprises a covalent bond to an amino acid of the polypeptide;
X is O or NR 7 ;
each R 4 , R 5 , and R 7 is selected, independently, from H, optionally substituted C 1-6 alkyl, C(O)R 8 , or a hydrolyzable linker Y that comprises a covalent bond to an amino acid of the polypeptide;
R 6 is H, optionally substituted C 1-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl,
R 8 is selected from optionally substituted C 1-6 alkyl or optionally substituted aryl;
each R 9 and R 10 is selected, independently, from H, optionally substituted C 1-6 alkyl, or optionally substituted aryl; and
wherein one and only one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 7 is Y.
2 . The compound of claim 1 , wherein each compound of Formula (I) is selected, independently, from
wherein
each R 2 is, independently, H, P(O)(OH) 2 , or —C(O)R 8 ;
each R 6 is, independently, CH 3 or 2-thiophene;
each R 8 is, independently, optionally substituted C 1-6 alkyl;
each Y is —C(O)(CH 2 ) n C(O)—; and
each n is, independently, 2, 3, or 4; and
wherein each Y is covalently bound to an amino acid.
3 . The compound of claim 1 , wherein Y is —C(O)(CH 2 ) n C(O)— and n is 2, 3, or 4, wherein each R 2 is —C(O)CH 2 N(CH 3 ) 2 , or wherein said amino acid sequence is covalently bonded to the compound having a structure according to Formula (I) through a second amino acid of said amino acid sequence.
4 . The compound of claim 3 , wherein said amino acid sequence is covalently bonded to the compound having a structure according to Formula (I) through a third amino acid of said amino acid sequence.
5 . The compound of claim 1 , wherein each amino acid covalently bonded to said hydrolyzable linker Y is attached via an amino-, a guanidino-, a hydroxyl-, a phenol-, or a thiol functional group of said amino acid.
6 . The compound of claim 5 , wherein each amino acid covalently bonded to said hydrolyzable linker Y is attached via an amino functional group or wherein said amino acid is lysine or threonine.
7 . The compound of claim 1 , wherein said amino acid sequence has at least 90% identity to the amino acid sequence of Angiopep-2 (SEQ ID NO:97).
8 . The compound of claim 1 , wherein said amino acid sequence comprises or consists of the amino acid sequence of Angiopep-2 (SEQ ID NO:97), Angiopep-4b, Angiopep-5, Angiopep-6, or Angiopep-7 (SEQ ID NOS:109-112).
9 . The compound of claim 7 , having the following structure
wherein each (-(Formula(I)) represents an optional covalent bond between the indicated amino acid and a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and wherein there is at least one covalent bond between an amino acid of the polypeptide and said compound of Formula (I).
10 . The compound of claim 9 , wherein the threonine at position 1 and the lysines at positions 10 and 15 of the polypeptide each comprise a covalent bond to a compound having a structure according to Formula (I), wherein each R 2 is, independently, H or P(O)(OH) 2 , or wherein each compound of Formula (I) has the following structure
11 . The compound of claim 10 , wherein n is 3.
12 . The compound of claim 9 , wherein each R 2 is a C-linked a-amino acid, wherein R 8 is a C 1-6 alkyl comprising an amino substituent, wherein —C(O)R 8 is dimethylglycine, or wherein each compound of Formula (I) is selected, independently, from
wherein each R 8A and R 8B is, independently, H, optionally substituted C 1-6 alkyl, or R 8A and R 8B combine to form an optionally substituted 3-7 membered ring.
13 . The compound of claim 12 , wherein each R 8A and R 8B is optionally substituted C 1-6 alkyl.
14 . The compound of claim 9 , wherein each compound of Formula (I) is
15 . The compound of claim 1 , wherein said compound has the following structure:
wherein each “Etoposide” represents etoposide 4′-dimethylglycine, or a pharmaceutically acceptable salt thereof, attached to the carbonyl group at the 2″ hydroxyl.
16 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17 . A method of treating a cancer, said method comprising administering to a patient a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18 . The method of claim 17 , further comprising the administration of a second therapeutic agent.
19 . The method of claim 18 , wherein said second therapeutic agent is a polypeptide comprising the sequence of Angiopep-2 (SEQ ID NO:97), and wherein said Angiopep-2 is conjugated to an anticancer agent.
20 . The method of claim 19 , wherein said anticancer agent is paclitaxel.
21 . The method of claim 20 , wherein said second therapeutic agent is ANG1005,
22 . The method of claim 17 , wherein said cancer is cancer of the brain.
23 . The method of claim 22 , wherein said cancer is a glioblastoma, a glioma, an acoustic neuroma, an adenoma, an astrocytoma, a choroid plexus papilloma, CNS lymphoma, ependymoma, a gangliocytoma, a ganglioglioma, a medulloblastoma (mdl), an anaplastic (malignant) meningioma, or neurofibromatosis.
24 . A method of making the compound of claim 1 , said method comprising the step of covalently binding a podophyllotoxin derivative to an amino acid sequence selected from SEQ ID NOS:1-105 and 107-116, or a functional derivative thereof, using a difunctional hydrolyzable linking group.
25 . The method of claim 24 , wherein
(a) said compound of Formula (I) is first combined with said difunctional hydrolyzable linking group to form a covalent adduct; and (b) the adduct of (a) is then combined with said amino acid sequence; wherein the adduct of (a) may be optionally purified prior to use in (b).
26 . The method of claim 25 , wherein 1.1-3.0 equivalents of said difunctional hydrolyzable linking group is used relative to the compound of Formula (I), the difunctional hydrolyzable linking group of (a) is glutaric anhydride, or wherein said compound of Formula (I) is etoposide, etoposide phosphate, etoposide-4′-dimethylglycine, or teniposide, or a pharmaceutically acceptable salt thereof.
27 . The method of claim 24 , further comprising the use of a peptide coupling agent.
28 . The method of claim 27 , wherein said peptide coupling agent is N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU).
29 . A compound, or a pharmaceutically acceptable salt thereof, comprising an amino acid sequence at least 70% identical to an amino acid sequence selected from the group consisting of SEQ ID NOS:1-105 and 107-116, or a functional derivative thereof, wherein said amino acid sequence comprises a covalent bond from an amino acid of said amino acid sequence to a doxorubicin derivative, and wherein said doxorubicin derivative is a compound having a structure according to Formula (II):
or a stereoisomer or pharmaceutically acceptable salt thereof, wherein
each X 1 , X 2 , X 3 , X 4 , and X 5 is selected, independently, from a covalent bond, O, or NR 25 ;
each R 17 , R 18 , R 19 , R 20 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 , is selected, independently, from H, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, or is a hydrolyzable linker Y; and
wherein one and only one of R 17 , R 18 , R 19 , R 20 , R 20 , R 21 , R 22 , R 23 , R 24 , and R 25 is Y.
30 . The compound of claim 29 , wherein the compound of Formula (II) has the following structure:
wherein
X 2 R 18 is H or NH 2 ;
X 3 R 19 is H or OH;
X 4 R 20 is H or optionally substituted C 1-3 alkyl;
Y is —C(O)(CH 2 ) n C(O)—;
and n is 2, 3, or 4.
31 . The compound of claim 30 , wherein said compound has the following structure:
32 . The compound of claim 29 , wherein Y is —C(O)(CH 2 ) n C(O)— and n is 2, 3, or 4, wherein said amino acid sequence is covalently bonded to a compound having a structure according to Formula (II) through a second amino acid of said amino acid sequence, or wherein said amino acid sequence is covalently bonded to a compound having a structure according to Formula (I) through a third amino acid of said amino acid sequence.
33 . The compound of claim 32 , wherein each amino acid covalently bonded to said hydrolyzable linker Y is attached via an amino-, a guanidino-, a hydroxyl-, a phenol-, or a thiol functional group of said amino acid.
34 . The compound of claim 33 , wherein each amino acid covalently bonded to said hydrolyzable linker Y is attached via an amino functional group or wherein said amino acid is lysine or threonine.
35 . The compound of claim 29 , wherein said amino acid sequence comprises or consists of the amino acid sequence of Angiopep-2 (SEQ ID NO:97).
36 . The compound of claim 35 , having the following structure
wherein each (-(Formula(II)) represents an optional covalent bond between the indicated amino acid and a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and wherein there is at least one covalent bond between an amino acid of the polypeptide and said compound of Formula (II).
37 . The compound of claim 36 , wherein the threonine at position 1 and the lysines at positions 10 and 15 of the polypeptide each comprise a covalent bond to a compound having a structure according to Formula (II) or wherein Y is —C(O)(CH2) n C(O)— and n is 2.
38 . A pharmaceutical composition comprising the compound of claim 29 and a pharmaceutically acceptable carrier.
39 . A method of treating a cancer, said method comprising administering to a patient a therapeutically effective amount of a compound of claim 29 .
40 . The method of claim 39 , further comprising the administration of a second therapeutic agent.
41 . The method of claim 39 , wherein said second therapeutic agent is a polypeptide comprising the sequence of Angiopep-2 (SEQ ID NO:97), and wherein said Angiopep-2 is conjugated to an anticancer agent.
42 . The method of claim 41 , wherein said anticancer agent is paclitaxel.
43 . The method of claim 42 , wherein said second therapeutic agent is ANG1005, which has the following structureCited by (0)
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