US2004242479A1PendingUtilityA1
Compounds capable of affecting differentiation, proliferation, regeneration, plasticity and survival of cells
Priority: Aug 17, 2001Filed: Aug 19, 2002Published: Dec 2, 2004
Est. expiryAug 17, 2021(expired)· nominal 20-yr term from priority
A61P 9/10A61P 9/00A61P 25/28A61P 25/02A61P 3/10A61P 25/24A61P 25/00A61P 25/16A61P 35/00A61P 25/14C07K 14/70503A61P 1/18C07K 2319/00A61K 38/00A61P 21/04A61P 15/08A61P 13/12A61P 17/02A61P 21/00
38
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to a compound comprising the third Immunoglobulin (Ig3) module, and/or the fourth Immunoglobulin (Ig4) module, and/or the fifth Immunoglobulin (Ig5), module, and/or the first Fibronectin III (Fn3,1) module, and/or the second Fibronectin III (Fn3,2) module of neural cell adhesion molecule (NCAM), or a fragment, or a variant thereof, capable of interacting with an Fibroblast Growth Factor (FGF) receptor and/or Adenosine-Tri-Phosphate (ATP) and/or L1, and thereby the compounds are capable of inducing differentiation, modulating proliferation, stimulate regeneration, neuronal plasticity and/or survival of cells. Further, the present invention relates to a pharmaceutical composition comprising said compound, a process of producing a pharmaceutical composition and the use of said compound.
Claims
exact text as granted — not AI-modified1 . A compound capable of interacting with Fibroblast Growth Factor (FGF) receptor comprising amino acid residues in the range of 3 to 100 amino acids, said compound comprising
(i) the second Fibronectin III (Fn3,2) module of the neural cell adhesion molecule (NCAM), or a fragment, or a variant thereof, and/or (ii) a fragment, or a variant of the first Fibronectin III (Fn3,1) module of NCAM, said fragment, or said variant being homologues to the FG-loop of the Fn3,2 module of NCAM.
2 . The compound according to claim 1 , wherein the FGF receptor is selected from the group consisting of FGF receptor I, FGF receptor II, FGF receptor III, and FGF receptor IV.
3 . The compound according to claim 1 , capable of stimulating FGF receptor signalling.
4 . The compound according to claim 3 , said compound stimulating FGF receptor I signalling.
5 . The compound according to claim 1 , comprising the second Fn 3,2 module of NCAM, or a fragment, or a variant thereof.
6 . The compound according to claim 1 , wherein (ii) comprising an amino acid sequence of the formula
L1-A-L2-B-L3-C-L4, wherein one of A, B, C is selected from a basic amino acid, one of A, B, C is selected from a hydrophobic amino acid, one of A, B, C is glycine, and L1, L2, L3, L4 may be selected from a chemical bond or an amino acid sequence having n amino acid residues, wherein n is an integer of from 0 to 5.
7 . The compound according to claim 6 , wherein B is glycine, A is a basic amino acid residue, and C is a hydrophobic amino acid residue.
8 . The compound according to claim 7 , wherein A is lysine (K), and C is leucine (L) or alanine (A).
9 . The compound according to claim 6 , comprising the sequence NGKGL (SEQ ID NO:26) or NGRGL (SEQ ID NO:27).
10 . The compound according to claim 1 , wherein (i) comprising an amino acid sequence of the formula
L1-A-L2-B-L3-C-L4-D-L5, wherein one of A, B, C, D is selected from a basic amino acid residue, one of A, B, C, D is selected from a hydrophobic amino acid residue, one of A, B, C, D is selected from an acidic amino acid residue, one of A, B, C, D is glycine, and L1, L2, L3, L4 and L5 may be selected from a chemical bond or an amino acid sequence having n amino acid residues, wherein n is an integer of from 0 to 5.
11 . The compound according to claim 1 , wherein said compound comprises a peptide homologous to the FG loop of the Fn3,2 module of the NCAM molecule, or a fragment, or a variant thereof.
12 . The compound according to claim 11 , wherein said compound comprises a peptide sequence having the motif A-E-N-Q-X-X-K, wherein X may be any amino acid residue.
13 . The compound according to claim 12 , wherein X is selected from Glutamine (Q),
Alanine (A) and/or Asparagine (N) and/or Glycine (G).
14 . The compound according to claim 1 , wherein said compound comprises at least one peptide sequence selected from the group consisting of
EVYVVAENQQGKSKA (SEQ ID NO 1), EVAVVAENQQGASAA (SEQ ID NO 2), VAENQQGKS (SEQ ID NO 3), AENQQGKS (SEQ ID NO 4), AENQQGK (SEQ ID NO 5), AENQAGK (SEQ ID NO 6), AMKEDGR (SEQ ID NO 7), ALNGKGLG (SEQ ID NO 8), AFNGRGLG (SEQ ID NO 9), LNGKGLG (SEQ ID NO 10), LNGKGL (SEQ ID NO 11), ALNGKG (SEQ ID NO 12), LNGNALGE (SEQ ID NO 13), LNGKALG (SEQ ID NO 14), ALNGKAL (SEQ ID NO 15), ALNLKGLGD (SEQ ID NO 16), LNGKELG (SEQ ID NO 17), LTGKGLAE (SEQ ID NO 18), LKGKGLEE (SEQ ID NO 19), LNSKGLVE (SEQ ID NO 20), LNGKALVE (SEQ ID NO 21), LAAKGLGE (SEQ ID NO 22), LDGKGL (SEQ ID NO 23), KGLGE (SEQ ID NO 24), DGKSLGE (SEQ ID NO 25), NGKGL (SEQ ID NO 26), NGRGL (SEQ ID NO 27), QAFNGRGLGP (SEQ ID NO 28), EVQAFNGRGLGPPAS (SEQ ID NO 29), AALNGKGLGE (SEQ ID NO 30), RLAALNGKGLGEIS (SEQ ID NO 31), ALNGKGAP (SEQ ID NO 32), VALNGKGAPR (SEQ ID NO 33), MYVALNGKGAPRRQ (SEQ ID NO 34), LNGRG (SEQ ID NO 35), LNGKG (SEQ ID NO 36), MYVALNGKGAPRRGQ (SEQ ID NO 37), MFLALDRRGGPRPGG (SEQ ID NO 38), MFLALDSQGIPRQGQ (SEQ ID NO 39), MFVALNQKGIPVRG (SEQ ID NO 40), MFVALNQKGIPVKG (SEQ ID NO 41), MFVALNQKGLPVKG (SEQ ID NO 42), WYVSVNGKGRPRRG (SEQ ID NO 43), YYVALNKDGTPREG (SEQ ID NO 44), YYVALNKDGSPREG (SEQ ID NO 45), YFVALNKDGTPRDG (SEQ ID NO 46), WYVALNKRGKAKRG (SEQ ID NO 47), WYLGLNKEGEIMKG (SEQ ID NO 48), WFLGLNKEGQIMKG (SEQ ID NO 49), TYIALSKYGRVKRG (SEQ ID NO 50), WFLGLNKEGQAMKG (SEQ ID NO 51), WFLGLNKEGQVMKG (SEQ ID NO 52), WYLGLDKEGQVMKG (SEQ ID NO 53), WYLGLDKEGRVMKG (SEQ ID NO 54), WYVALKRTGQYKLG (SEQ ID NO 55), WFVGLKKNGSCKRG (SEQ ID NO 56), ANRYLAMKEDGRLLAS (SEQ ID NO 57), TGQYLAMDTEGLLYGS (SEQ ID NO 58), TGQYLAMDTDGLLYGS (SEQ ID NO 59), TGQYLAMDTSGLLYGS (SEQ ID NO 60), TGQFLAMDTDGLLYGS (SEQ ID NO 61), SRFFVAMSSKGKLYGS (SEQ ID NO 62), SRFFVAMSSRGKLFGV (SEQ ID NO 63), SRFFVAMSSRGRLYGS (SEQ ID NO 64), SGLFVAMNSKGKLYGS (SEQ ID NO 65), SNKFLAMSKKGKLHAS (SEQ ID NO 66), SALFVAMNSKGRLYAT (SEQ ID NO 67), SALFIAMNSKGRLYTT (SEQ ID NO 68), SGRYLAMNKRGRLYAS (SEQ ID NO 69), SEYYLAMNKEGKLYAK (SEQ ID NO 70), SEYYLAMNKQGLYAK (SEQ ID NO 71), SEFYLAMNKEGKLYAK (SEQ ID NO 72), SGLYLGMNEKGELYGS (SEQ ID NO 73), SGLYLGMNDKGELYGS (SEQ ID NO 74), SGLYLGMNERGELYGS (SEQ ID NO 75), SGLYLGMNERGELFGS (SEQ ID NO 76), SNYYLAMNKKGKLYGS (SEQ ID NO 77), SGFYVAMNRRGRLYGS (SEQ ID NO 78), TGLYIAMNGEGYLYPS (SEQ ID NO 79), ASLYVAMNGEGYLYSS (SEQ ID NO 80), TKLYLAMNSEGYLYTS (SEQ ID NO 81), TGLYICMNKKGKLIAKS (SEQ ID NO 82), LGHYMAMNAEGLLYSS (SEQ ID NO 83), TEFYLCMNRKGKLVGK (SEQ ID NO 84), SVRYLCMGADGKMQGL (SEQ ID NO 85), WFVGLKKNGS[[ ]]CKRG (SEQ ID NO 86), WYVALKRTGQ[[ ]]YKLG (SEQ ID NO 87), WYVSVNGKGR[[ ]]PRRG (SEQ ID NO 88), GMFIALSKNG[[ ]]KTKKG (SEQ ID NO 89), GMFMALSKNG[[ ]]RTKKG (SEQ ID NO 91), GMFIALSKNG[[ ]]KAKKG (SEQ ID NO 92), WYVALNKRGK[[ ]]AKRG (SEQ ID NO 93), TYIALSKYGR[[ ]]VKRG (SEQ ID NO 94), MFVALNQKGI[[ ]]PVRG (SEQ ID NO 95), MFVALNQKGI[[ ]]PVKG (SEQ ID NO 96), MFVALNQKGL[[ ]]PVKG (SEQ ID NO 97), WYMAFTRKGR[[ ]]PRKG (SEQ ID NO 98), YYVALNKDGT[[ ]]PREG (SEQ ID NO 99), MYVALNGKGA[[ ]]PRRGQ (SEQ ID NO 100), WYLGLDKEGQ[[ ]]VMKG (SEQ ID NO 101), WYLGLDKEGR[[ ]]VMKG (SEQ ID NO 102), WFLGLNKEGQ[[ ]]IMKG (SEQ ID NO 103), WYLGLNKEGE[[ ]]IMKG (SEQ ID NO 104), WFLGLNKEGQ[[ ]]AMKG (SEQ ID NO 105), WFLGLNKEGQ[[ ]]VMKG (SEQ ID NO 106), YYVALNKDGS[[ ]]PREG (SEQ ID NO 107), WFMAFTRQGR[[ ]]PRQ (SEQ ID NO 108), WFVGLKKNGS[[ ]]CKRG (SEQ ID NO 109), WYVGFTKKGR[[ ]]PRKG (SEQ ID NO 110), YFVALNKDGT[[ ]]PRDG (SEQ ID NO 111), MFLALDRRGG[[ ]]PRPGG (SEQ ID NO 112), MFLALDSQGI[[ ]]PRQGQ (SEQ ID NO 113), TGQYLAMDTE[[ ]]GLLYGS (SEQ ID NO 114), TGQYLAMDTD[[ ]]GLLYGS (SEQ ID NO 115), TGQYLAMDTS[[ ]]GLLYGS (SEQ ID NO 116), TGQFLAMDTD[[ ]]GLLYGS (SEQ ID NO 118), ANRYLAMKED[[ ]]GRLLAS (SEQ ID NO 119), SGRYLAMNKR[[ ]]GRLYAS (SEQ ID NO 120), SRFFVAMSSK[[ ]]GKLYGS (SEQ ID NO 121), SRFFVAMSSR[[ ]]GKLFGV (SEQ ID NO 122), SRFFVAMSSR[[ ]]GRLYGS (SEQ ID NO 123), SGLFVAMNSK[[ ]]GKLYGS (SEQ ID NO 124), SNKFLAMSKK[[ ]]GKLHAS (SEQ ID NO 125), SALFVAMNSK[[ ]]GRLYAT (SEQ ID NO 126), SALFIAMNSK[[ ]]GRLYTT (SEQ ID NO 127), SEYYLAMNKE[[ ]]GKLYAK (SEQ ID NO 128), SEYYLAMNKQ[[ ]]GLYAK (SEQ ID NO 129), SEFYLAMNKE[[ ]]GKLYAK (SEQ ID NO 130), TGLYICMNKK[[ ]]GKLIAKS (SEQ ID NO 131), SGLYLGMNEK[[ ]]GELYGS (SEQ ID NO 132), SNYYLAMNKK[[ ]]GKLYGS (SEQ ID NO 133), LGHYMAMNAE[[ ]]GLLYSS (SEQ ID NO 134), ASLYVAMNGE[[ ]]GYLYSS (SEQ ID NO 135), TKLYLAMNSE[[ ]]GYLYTS (SEQ ID NO 136), TGLYIAMNGE[[ ]]GYLYPS (SEQ ID NO 137), SVRYLCMSAD[[ ]]GKIYG (SEQ ID NO 138), SGLYLGMNER[[ ]]GELYGS (SEQ ID NO 139), SGLYLGMNER[[ ]]GELFGS (SEQ ID NO 140), SEKYICMNKR[[ ]]GKLIG (SEQ ID NO 141), TEFYLCMNRK[[ ]]GKLVGK (SEQ ID NO 142), SVRYLCMGAD[[ ]]GKMQGL (SEQ ID NO 143), SGLYLGMNDK[[ ]]GELYGS (SEQ ID NO 144), TSRFLCQRPD[[ ]]GALYG (SEQ ID NO 145), ASRFLCQQPD[[ ]]GALYG (SEQ ID NO 146), SGFYVAMNRR[[ ]]GRLYGS (SEQ ID NO 147), SRRYLCMDFR[[ ]]GNIFGS (SEQ ID NO 148), TRRFLCMDLH[[ ]]GNIFGS (SEQ ID NO 149), GLKKNGSC (SEQ ID NO 150), ALKRTGQY (SEQ ID NO 151), SVNGKGRP (SEQ ID NO 152), IALSKNGKT (SEQ ID NO 153), MALSKNGRT (SEQ ID NO 154), IALSKNGKA (SEQ ID NO 155), ALNKRGKA (SEQ ID NO 156), ALSKYGRV (SEQ ID NO 157), ALNQKGIP (SEQ ID NO 158), ALNQKGLP (SEQ ID NO 159), AFTRKGRP (SEQ ID NO 160), ALNKDGTP (SEQ ID NO 161), ALNGKGAPR (SEQ ID NO 162), GLDKEGQV (SEQ ID NO 163), GLDKEGRV (SEQ ID NO 164), GLNKEGQI (SEQ ID NO 165), GLNKEGEI (SEQ ID NO 166), GLNKEGQA (SEQ ID NO 167), GLNKEGQV (SEQ ID NO 168), ALNKDGSP (SEQ ID NO 169), AFTRQGR (SEQ ID NO 170), GLKKNGSC (SEQ ID NO 171), GFTKKGRP (SEQ ID NO 172), ALNKDGTP (SEQ ID NO 173), ALDRRGGPR (SEQ ID NO 174), ALDSQGIPR (SEQ ID NO 175), AMDTDGL (SEQ ID NO 176), AMDTEGL (SEQ ID NO 177), AMDTSGL (SEQ ID NO 178), AMKEDGR (SEQ ID NO 179), AMNKRGR (SEQ ID NO 180), AMSSKGK (SEQ ID NO 181), AMSSRGK (SEQ ID NO 182), AMNSKGK (SEQ ID NO 183), AMSKKGK (SEQ ID NO 184), AMNSKGR (SEQ ID NO 185), AMNKEGK (SEQ ID NO 186), AMNKEGK (SEQ ID NO 187), AMNKQGL (SEQ ID NO 188), CMNKKGK (SEQ ID NO 189), GMNEKGE (SEQ ID NO 190), AMNKKGK (SEQ ID NO 191), AMNAEGL (SEQ ID NO 192), AMNGEGY (SEQ ID NO 193), AMNSEGY (SEQ ID NO 194), AMNGEGY (SEQ ID NO 195), CMSADGK (SEQ ID NO 196), GMNERGE (SEQ ID NO 197), CMNKRGK (SEQ ID NO 198), CMNRKGK (SEQ ID NO 199), CMGADGK (SEQ ID NO 200), GMNDKGE (SEQ ID NO 201), LCQRPDG (SEQ ID NO 202), LCQQPDG (SEQ ID NO 203), AMNRRGR (SEQ ID NO 204), CMDFRGN (SEQ ID NO 205), and CMDLHGN (SEQ ID NO 206).
15 . The compound according to claim 10 , wherein the amino acid sequence has the formula
AENQ-L4-G, wherein L4 is as defined in claim 10 .
16 . The compound according to claim 1 , wherein (i) comprising an amino acid sequence of the formula
A-B-L3-L4-C-L4, wherein A is a hydrophobic amino acid residue, B is an acidic amino acid residue, L3 is one or more hydrophilic amino acid residue(s), L4 is an amino acid sequence as defined in claim 10 for L4, and C is glycine.
17 . The compound according to claim 1 comprising a sequence of the formula L1-A-L2-B-L3-C-L4-D-L5-E-L6, wherein
at least one of L1, L2, L3, or L4 comprises the amino acid residue Y and one of the other comprises the amino acid residue K,
L5 and/or L6 individually is K, and A, B, C, D, E is any amino acid, with the proviso, that the distance between Y and K is at least 5 amino acids, such as at least 7 amino acid residues, such as at least 9 amino acid residues, such as at least 11 amino acid residue.
18 . (Cancelled)
19 . The compound according to claim 1 , wherein the compound is a dimer or a multimer, and thereby comprises a plurality of monomers.
20 . (Cancelled)
21 . The compound according to claim 19 , wherein the compound comprises monomers independently capable of stimulating FGF receptor signalling and/or modulating proliferation and/or inducing differentiation and/or stimulating regeneration, neuronal plasticity and/or survival of cells presenting an FGF receptor.
22 . The compound according to claim 19 , wherein the monomers are homologous.
23 . The compound according to claim 19 , wherein the monomers are heterologous.
24 . The compound according to claim 21 , wherein the FGF receptor signalling is measured as phosphorylation of the FGF receptor when a predetermined concentration of the compound is applied to cells expressing the FGF receptor.
25 . The compound according to claim 24 , wherein the degree of phoshorylation is at least 20% above the control value.
26 . The compound according to claim 24 , wherein the predetermined concentration of said compound is 0.1-200 μM.
27 . The compound according to claim 1 , consisting of 10-90 amino acid residues.
28 . The compound according to claim 1 , consisting of 3 to 20 amino acid residues.
29 . The compound according to claim 1 , capable of modulating proliferation and/or differentiation and/or regeneration and/or neuronal plasticity and/or survival of cells.
30 . A pharmaceutical composition comprising at least one compound as defined in claim 1 .
31 . The pharmaceutical composition according to claim 30 , wherein the compound is the NCAM Fn3,2 module, or a fragment thereof, or a variant thereof.
32 . The pharmaceutical composition according to claim 30 , wherein the compounds are formulated as dimers.
33 . The pharmaceutical composition according to claim 30 , wherein the compounds are formulated as multimers.
34 . The pharmaceutical composition according to claim 30 formulated for oral, percutaneous, intramuscular, intravenous, intracranial, intrathecal, intracerebroventricular, intranasal or pulmonal administration.
35 . The method according to claim 52 , wherein the administration is continuous.
36 . A process of producing a pharmaceutical composition, comprising mixing an effective amount of one or more of the compounds according to claim 1 , with one or more pharmaceutically acceptable additives or carriers.
37 . The method according to claim 52 , wherein the compound as defined in claim 1 is used in combination with a prosthetic device.
38 . The method according to claim 37 , wherein the device is a prosthetic nerve guide.
39 . The method according to claim 38 , wherein the prosthetic nerve guide is characterised in that it comprises at least one compound as defined in claim 1 .
40 - 42 . (Cancelled)
43 . The method of claim 52 which comprises treatment of a disease or condition of the central and peripheral nervous system.
44 . The method according to claim 41 , which comprises treatment of a disease or condition of the muscles; or treatment of a disease or condition of the gonads, the pancreas, or the kidney.
45 . The method according to claim 52 , which prevents cell death of heart muscle cells.
46 . The method according to claim 45 , which results in revascularisation.
47 . The method according to claim 52 , which promotes wound-healing.
48 . The method according to claims 52 , which inhibits angiogenesis.
49 . The method according to claim 43 , wherein the disease or condition is a cancer.
50 . The method according to claim 43 , which results stimulation of the ability to learn and/or of the short and/or long term memory.
51 . The method according to claim 43 , which modulates proliferation and/or differentiation and/or regeneration and/or neuronal plasticity and/or survival of cells.
52 . A method of treating a disease or condition which is treatable with a compound of claim 1 , which comprises administering to a subject suffering from said disease or condition a therapeutically effective amount of at least one compound of claim 1.Join the waitlist — get patent alerts
Track US2004242479A1 — get alerts on status changes and closely related new filings.
We store only your email — no account needed. See our privacy policy.