METHODS AND COMPOUNDS FOR TARGETING SORTILIN RECEPTORS AND INHIBITING VASCULOGENIC MIMICRY
The present disclosure relates to peptide compounds and conjugate compounds, processes, methods and uses thereof for treatment of cancer or aggressive cancer. For example, the compounds can comprise compounds of formula X 1 X 2 X 3 X 4 X 5 GVX 6 AKAGVX 7 NX 8 FKSESY (I) (SEQ ID NO: 1) (X 9 ) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2) YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III) (SEQ ID NO: 3) YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4) IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5) IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6) IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7) GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8) GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9) GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10) YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11) YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12) YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13) wherein X 1 to X 21 and n can have various different values and 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, for use in inhibiting vasculogenic mimicry and/or for treating a cancer.
1 - 50 . (canceled)
51 . A method of inhibiting vasculogenic mimicry in cancerous tissues formed by cancerous cells expressing Sortilin comprising administering to a subject in need thereof a therapeutically effective amount of at least one conjugate compound having the formula of A-(B) n ,
wherein
n is 1, 2, 3 or 4;
A is a peptide compound having at least 80% sequence identity to a compound chosen from compounds of formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII) and formula (XIII):
(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 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
B is at least one therapeutic agent, wherein B is connected to A, optionally via a linker,
optionally the peptide compound is cyclic.
52 . The method of claim 51
wherein B is connected to A at a free amine of a lysine residue of said peptide compound, optionally via a linker, or at an N-terminal position of said peptide compound, optionally via a linker.
53 - 65 . (canceled)
66 . The method of claim 51 , 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).
67 . The method of claim 51 , wherein the peptide compound is represented by formula (X) and consists of the amino acid sequence of SEQ ID NO: 10.
68 . The method of claim 51 , wherein the peptide compound is represented by formula (XI) and consists of the amino acid sequence of SEQ ID NO: 11.
69 . The method of claim 51 , wherein the peptide compound comprises at least one protecting group that is acetyl or succinyl.
70 . The method of claim 51 , wherein the peptide compound is represented by Formula (XXXVIII), Formula (XXXIX), Formula (XL), Formula (XLI) or Formula (XLII):
(XXXVIII)
(SEQ ID NO: 14)
Acetyl-GVRAKAGVRNMFKSESY
(XXXIX)
(SEQ ID NO: 15)
Acetyl-GVRAKAGVRN(Nle)FKSESY
(XL)
(SEQ ID NO: 16)
Acetyl-YKSLRRKAPRWDAPLRDPALRQLL
(XLI)
(SEQ ID NO: 17)
Acetyl-YKSLRRKAPRWDAYLRDPALRQLL
(XLII)
(SEQ ID NO: 18)
Acetyl-YKSLRRKAPRWDAYLRDPALRPLL.
71 . The method of claim 51 , wherein B is connected to A via a linker, optionally a cleavable linker or a non-cleavable linker.
72 . The method of claim 51 , wherein the at least one therapeutic agent is a phytochemical agent or an anticancer agent.
73 . The method of claim 72 , wherein the anticancer agent is docetaxel, doxorubicin, cabazitaxel, maytansinoids, auristatins, calicheamicins, amatoxins, amanitin, or aldoxorubicin.
74 . The method of claim 73 , wherein the anticancer agent is docetaxel.
75 . The method of claim 74 , wherein the conjugate compound is represented by formula (XIX) or (XXIII):
GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY Formula (XIX)
that comprises the peptide compound of SEQ ID NO: 10 wherein each lysine residue has a docetaxel molecule connected thereto; or
Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY Formula (XXIII)
that comprises the peptide compound of SEQ ID NO: 15 wherein each lysine residue has a docetaxel molecule connected thereto.
76 . The method of claim 73 , wherein the anticancer agent is doxorubicin.
77 . The method of claim 76 , wherein the conjugate compound is represented by formula (XXVI) or (XXVIII):
GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY Formula (XXVI)
that comprises the peptide compound of SEQ ID NO: 10 wherein each lysine residue has a doxorubicin molecule connected thereto; or
Acetyl-GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY Formula (XXVIII)
that comprises the peptide compound of SEQ ID NO: 15 wherein each lysine residue has a doxorubicin molecule connected thereto.
78 . The method of claim 73 , wherein the anticancer agent is aldoxorubicin.
79 . The method of claim 78 , wherein the conjugate compound is represented by the formula (LI) or (LII):
GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin) Formula (LI)
that comprises the peptide compound of SEQ ID NO: 23 wherein cysteine residue has an aldoxorubicin molecule connected thereto, or
that comprises the peptide compound of SEQ ID NO: 10 wherein a cysteine residue is added to C-terminal of said peptide compound, and wherein the cysteine residue has an aldoxorubicin molecule connected thereto; or
Acetyl-GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin) Formula (LII)
that comprises the peptide compound of SEQ ID NO: 24 wherein cysteine residue has an aldoxorubicin molecule connected thereto, or
that comprises the peptide compound of SEQ ID NO: 15 wherein a cysteine residue is added to C-terminal of said peptide compound, and wherein the cysteine residue has an aldoxorubicin molecule connected thereto.
80 . The method of claim 72 , wherein the phytochemical agent is curcumin.
81 . The method of claim 80 , wherein wherein the conjugate compound is chosen from compounds of formula (XIV), (XV), (XVI) or (XVII):
GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY Formula (XIV)
that comprises the peptide compound having SEQ ID NO: 10 wherein each lysine residue has a curcumin molecule connected thereto;
YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL Formula (XV)
that comprises the peptide compound having SEQ ID NO: 11 wherein each lysine residue has a curcumin molecule connected thereto;
Acetyl-GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY Formula (XVI)
that comprises the peptide compound of SEQ ID NO: 15 wherein each lysine residue has a curcumin molecule connected thereto;
Acetyl-YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL Formula (XVII)
that comprises the peptide compound of SEQ ID NO: 16 wherein each lysine residue has a curcumin molecule connected thereto.