Peptide compounds and peptide conjugates for the treatment of cancer through receptor-mediated chemotherapy
The present disclosure relates to peptide compounds and conjugate compounds, processes, methods and uses thereof for treating cancer and increasing cellular internalization of said peptide compounds. The peptide compounds are selected from the following group consisting of; GVRAKAGVRNMFKSESY as set forth in SEQ ID NO: 9; GVRAKAGVRN(Nle)FKSESY as set forth in SEQ ID NO: 10; and YKSLRRKAPRWDAPLRDPALRQLL as set forth in SEQ ID NO: 11; and wherein at least one protecting group and/or at least one labelling agent is connected to said peptide compound.
1. A conjugate compound having the formula A-(B) n
wherein
n is 1, 2, 3, or 4;
A is a peptide compound, wherein said peptide compound is optionally protected by a protecting group; and
B is a therapeutic agent, wherein B is connected to A at a free amine of said peptide compound, at an N-terminal position of said peptide compound, at a free —SH of said peptide compound, or at a free carboxyl of said peptide compound;
wherein the peptide compound is a compound chosen from compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII) and if chosen from formulas (V) through (XIII) has at least 80% sequence identity to those compounds:
(I)
(SEQ ID NO: 1)
X 1 X 2 X 3 X 4 X 5 GVX 6 AKAGVX 7 NX 8 FKSESY
(II)
(SEQ ID NO: 2)
(X 9 ) m GVX 10 AKAGVX 11 NX 12 FKSESY
(III)
(SEQ ID NO: 3)
YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L
(IV)
(SEQ ID NO: 4)
YKX 18 LRR(X 19 ) m PLRDPALRX 20 X 21 L
(V)
(SEQ ID NO: 5)
IKLSGGVQAKAGVINMDKSESM
(VI)
(SEQ ID NO: 6)
IKLSGGVQAKAGVINMFKSESY
(VII)
(SEQ ID NO: 7)
IKLSGGVQAKAGVINMFKSESYK
(VIII)
(SEQ ID NO: 8)
GVQAKAGVINMFKSESY
(IX)
(SEQ ID NO: 9)
GVRAKAGVRNMFKSESY
(X)
(SEQ ID NO: 10)
GVRAKAGVRN(Nle)FKSESY
(XI)
(SEQ ID NO: 11)
YKSLRRKAPRWDAPLRDPALRQLL
(XII)
(SEQ ID NO: 12)
YKSLRRKAPRWDAYLRDPALRQLL
(XIII)
(SEQ ID NO: 13)
YKSLRRKAPRWDAYLRDPALRPLL
wherein
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently chosen from any amino acid;
X 16 , X 17 , X 20 and X 21 are independently chosen from Q, P, Y, I and L;
m is 0, 1, 2, 3, 4 or 5;
when X 9 is present more than once, each of said X 9 is independently chosen from any amino acid;
when X 19 is present more than once, each of said X 19 is independently chosen from any amino acid,
wherein at least one protecting group and/or at least one labelling agent is optionally connected to said peptide compound at an N- and/or C-terminal end; and
Wherein the B is connected to A via a cleavable linker or a non-cleavable linker.
2. The conjugate of claim 1 , wherein the peptide compound is represented by formula (IX) and consists of the amino acid sequence of SEQ ID NO: 9.
3. The conjugate of claim 1 , wherein the peptide compound is represented by formula (X) and consists of the amino acid sequence of SEQ ID NO: 10.
4. The conjugate of claim 1 , wherein the peptide compound is represented by formula (XI) and consists of the amino acid sequence of SEQ ID NO: 11.
5. The conjugate of claim 1 , wherein the peptide compound has at least 90% sequence identity to the compound chosen from compounds of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII).
6. The conjugate of claim 1 , wherein the peptide compound comprises at least one protecting group that is acetyl or succinyl.
7. The conjugate of claim 1 , wherein the peptide compound is represented by Formula (XXXVIII), Formula (XXXIX), Formula (XXXX), Formula (XXXXI) or Formula (XXXXII):
(XXXVIII)
(SEQ ID NO: 14)
Acetyl-GVRAKAGVRNMFKSESY
(XXXIX)
(SEQ ID NO: 15)
Acetyl-GVRAKAGVRN(Nle)FKSESY
(XXXX)
(SEQ ID NO: 16)
Acetyl-YKSLRRKAPRWDAPLRDPALRQLL
(XXXXI)
(SEQ ID NO: 17)
Acetyl-YKSLRRKAPRWDAYLRDPALRQLL
(XXXXII)
(SEQ ID NO: 18)
Acetyl-YKSLRRKAPRWDAYLRDPALRPLL.
8. The conjugate of claim 1 , wherein B is connected to A at a free amine of a lysine residue of said peptide compound, or at an N-terminal position of said peptide compound.
9. A conjugate compound having the formula A-(B) n
wherein
n is 1, 2, 3, or 4;
A is a peptide compound, wherein said peptide compound is optionally protected by a protecting group; and
B is a therapeutic agent, wherein B is connected to A at a free amine of said peptide compound, at an N-terminal position of said peptide compound, at a free —SH of said peptide compound, or at a free carboxyl of said peptide compound;
wherein the peptide compound is a compound chosen from compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII) and if chosen from formulas (V) through (XIII) has at least 80% sequence identity to those compounds:
(I)
(SEQ ID NO: 1)
X 1 X 2 X 3 X 4 X 5 GVX 6 AKAGVX 7 NX 8 FKSESY
(II)
(SEQ ID NO: 2)
(X 9 ) m GVX 10 AKAGVX 11 NX 12 FKSESY
(III)
(SEQ ID NO: 3)
YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L
(IV)
(SEQ ID NO: 4)
YKX 18 LRR(X 19 ) m PLRDPALRX 20 X 21 L
(V)
(SEQ ID NO: 5)
IKLSGGVQAKAGVINMDKSESM
(VI)
(SEQ ID NO: 6)
IKLSGGVQAKAGVINMFKSESY
(VII)
(SEQ ID NO: 7)
IKLSGGVQAKAGVINMFKSESYK
(VIII)
(SEQ ID NO: 8)
GVQAKAGVINMFKSESY
(IX)
(SEQ ID NO: 9)
GVRAKAGVRNMFKSESY
(X)
(SEQ ID NO: 10)
GVRAKAGVRN(Nle)FKSESY
(XI)
(SEQ ID NO: 11)
YKSLRRKAPRWDAPLRDPALRQLL
(XII)
(SEQ ID NO: 12)
YKSLRRKAPRWDAYLRDPALRQLL
(XIII)
(SEQ ID NO: 13)
YKSLRRKAPRWDAYLRDPALRPLL
wherein
X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently chosen from any amino acid;
X 16 , X 17 , X 20 and X 21 are independently chosen from Q, P, Y, I and L;
m is 0, 1, 2, 3, 4 or 5;
when X 9 is present more than once, each of said X 9 is independently chosen from any amino acid;
when X 19 is present more than once, each of said X 19 is independently chosen from any amino acid,
wherein at least one protecting group and/or at least one labelling agent is optionally connected to said peptide compound at an N- and/or C-terminal end; and
wherein the at least one therapeutic agent is an anticancer agent.
10. The conjugate compound of claim 9 , wherein the anticancer agent is docetaxel, cabazitaxel, paclitaxel, doxorubicin or daunomycin.
11. The conjugate compound of claim 9 , wherein the anticancer agent is docetaxel.
12. The conjugate compound of claim 9 , wherein the conjugate compound is chosen from compounds of formula (XIV), formula (XV), formula (XVI), formula (XVII) and formula (XVIII):
IK(docetaxel)LSGGVQAK(docetaxel)AGVINMFK(docetaxel)SESY (XIV)
that comprises the peptide compound having SEQ ID NO: 6 wherein each lysine residue has a docetaxel molecule connected thereto;
GVQAK(docetaxel)AGVINMFK(docetaxel)SESY (XV)
that comprises the peptide compound having SEQ ID NO: 8 wherein each lysine residue has a docetaxel molecule connected thereto;
GVRAK(docetaxel)AGVRNMFK(docetaxel)SESY (XVI)
that comprises the peptide compound having SEQ ID NO: 9 wherein each lysine residue has a docetaxel molecule connected thereto;
GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY (XVII)
that comprises the peptide compound having SEQ ID NO: 10 wherein each lysine residue has a docetaxel molecule connected thereto; and
YK(docetaxel)SLRRK(docetaxel)APRWDAPLRDPALRQL (XVIII)
that comprises the peptide compound having SEQ ID NO: 11 wherein each lysine residue has a docetaxel molecule connected thereto.
13. The conjugate compound of claim 12 , wherein the conjugate compound is represented by formula (XVII).
14. The conjugate compound of claim 12 , wherein the conjugate compound is represented by formula (XVIII).
15. The conjugate compound of claim 8 , wherein the conjugate compound is chosen from compounds of formula (XXIII), formula (XXIV) and formula (XXV):
GVQAK(doxorubicin)AGVINMFK(doxorubicin)SESY (XXIII)
that comprises the peptide compound having SEQ ID NO: 8 wherein each lysine residue has a doxorubicin molecule connected thereto;
GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY (XXIV)
that comprises the peptide compound having SEQ ID NO: 10 wherein each lysine residue has a doxorubicin molecule connected thereto; and
YK(doxorubicin)SLRRK(doxorubicin)APRWDAPLRDPALRQLL (XXV)
that comprises the peptide compound having SEQ ID NO: 11 wherein each lysine residue has a doxorubicin molecule connected thereto.
16. The conjugate compound of claim 9 , wherein the conjugate compound is chosen from compounds of formula (XXVIII), formula (XXIX) and (XXX):
GVRAK(cabazitaxel)AGVRNMFK(cabazitaxel)SESY (XXVIII)
that comprises the peptide compound having SEQ ID NO: 9 wherein each lysine residue has a cabazitaxel molecule connected thereto;
GVRAK(cabazitaxel)AGVRN(Nle)FK(cabazitaxel)SESY (XXIX)
that comprises the peptide compound having SEQ ID NO: 10 wherein each lysine residue has a cabazitaxel molecule connected thereto; and
YK(cabazitaxel)SLRRK(cabazitaxel)APRWDAPLRDPALRQLL (XXX)
that comprises the peptide compound having SEQ ID NO: 11 wherein each lysine residue has a cabazitaxel molecule connected thereto.
17. The conjugate of claim 9 , wherein the peptide compound is represented by formula (IX) and consists of the amino acid sequence of SEQ ID NO: 9.
18. The conjugate of claim 9 , wherein the peptide compound is represented by formula (X) and consists of the amino acid sequence of SEQ ID NO: 10.
19. The conjugate of claim 9 , wherein the peptide compound is represented by formula (XI) and consists of the amino acid sequence of SEQ ID NO: 11.
20. The conjugate of claim 9 wherein the peptide compound has at least 90% sequence identity to the compound chosen from compounds of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII).
21. The conjugate of claim 9 , wherein the peptide compound comprises at least one protecting group that is acetyl or succinyl.
22. The conjugate of claim 9 , wherein the peptide compound is represented by Formula (XXXVIII), Formula (XXXIX), Formula (XXXX), Formula (XXXXI) or Formula (XXXXII):
(XXXVIII)
(SEQ ID NO: 14)
Acetyl-GVRAKAGVRNMFKSESY
(XXXIX)
(SEQ ID NO: 15)
Acetyl-GVRAKAGVRN(Nle)FKSESY
(XXXX)
(SEQ ID NO: 16)
Acetyl-YKSLRRKAPRWDAPLRDPALRQLL
(XXXXI)
(SEQ ID NO: 17)
Acetyl-YKSLRRKAPRWDAYLRDPALRQLL
(XXXXII)
(SEQ ID NO: 18)
Acetyl-YKSLRRKAPRWDAYLRDPALRPLL.
23. The conjugate compound of claim 9 , wherein the conjugate compound is a compound of formula (XXI):
Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY (XXI)
that comprises the peptide compound having SEQ ID NO: 15 wherein each lysine residue has a docetaxel molecule connected thereto.
24. The conjugate compound of claim 9 , wherein the conjugate compound is a compound of formula (XXII):
Acetyl-YK(docetaxel)SLRRK(docetaxel)APRWDAPLRDPALRQLL (XXII)
that comprises the peptide compound having SEQ ID NO: 16 wherein each lysine residue has a docetaxel molecule connected thereto.
25. The conjugate compound of claim 9 , wherein the conjugate compound is a compound of formula (XXVI):
Acetyl-GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY (XXVI)
that comprises the peptide compound having SEQ ID NO: 15 wherein each lysine residue has a docetaxel molecule connected thereto.
26. A conjugate compound having the following structure:
that comprises the peptide compound having SEQ ID NO: 15 wherein each lysine reside has a docetaxel molecule connected thereto.