Peptide compounds useful for modulating FGF receptor activity

Details Peptide compounds useful for modulating FGF receptor activity Peptide compounds useful for modulating FGF receptor activity

1996-11-12

2001-04-10

Saoud, Christine (Department: 1646)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S013800, C514S014800, C514S015800, C530S324000, C530S325000, C530S326000, C530S327000

Reexamination Certificate

active

06214795

ABSTRACT:

BACKGROUND OF THE INVENTION
The fibroblast growth factor (FGF) family consists of closely related polypeptide mitogens. This family includes at least seven members based on amino acid sequence homologies: basic FGF (Esch et al. (1985)
Proc. Natl. Acad. Sci. USA
82:6507-6511; Abraham et al. (1986)
Science
233:545-548; Abraham et al. (1986)
EMBO J.
5:2523-2528; Kurokawa et al. (1987)
FEBS Lett.
213:189-194), acidic FGF (Gimenez-Gallago et al. (1985)
Science
230:1385-1388; Thomas et al. (1985)
Proc. Natl. Acad. Sci. USA
82:6409-6413; Jaye et al. (1986)
Science
233:543-545), int-2 (Moore et al. (1986)
EMBO J.
5:919-924), hst (Kaposi sarcoma FGF) (Taira et al. (1987)
Proc. Natl. Acad. Sci. USA
84:2980-2984; Bovi et al. (1987)
Cell
50:729-737), FGF-5 (Zhan et al. (1988)
Mol. Cell. Biol.
8:3487-3495), FGF-6 (Marics et al. (1989)
Oncogene
4:335-340) and keratinocyte growth factor (KGF)(Finch et al. (1989)
Science
245:752-755; Rubin et al. (1989)
Proc. Natl. Acad. Sci. USA
86:802-806).
The pleiotropic effects of the FGF family members include proliferative activity for a wide variety of cells, neurotrophic activity and angiogenic activity (Gospodarowicz et al. (1986)
Cell. Differ.
19:1-17; Morrison et al. (1986)
Proc. Natl. Acad. Sci. USA
83:7537-7541; Walicke et al. (1986)
Proc. Natl. Acad. Sci. USA
83:3012-3016; Folkman and Klagsbrun (1987)
Science
235:442-447; Thomas (1987)
FASEB J.
1:434-440; Anderson et al. (1988)
Nature
332:360-361; Burgess and Maciag (1989)
Annu. Rev. Biochem.
58:575-606). The FGFs also have the ability to influence the differentiation of a variety of cell types, exhibiting both differentiation-inducing and differentiation-inhibiting effects (Linkhart et al. (1981)
Dev. Biol.
86:19-30; Serrero and Khoo (1982)
Anal. Biochem.
120:351-359; Broad and Ham (1983)
Eur. J. Biochem.
135:33-39; Lathrop et al. (1985)
J. Cell. Biol.
100:1540-1547; Togari et al. (1985)
J. Neurosci.
5:307-316; Wagner and D'Amore (1986)
J. Cell. Biol.
103:1363-1367; Anderson et al. (1988)
Nature
332:360-361). FGFs are also thought to play an important role in embryonal development (Kimelman and Kirschner (1987)
Cell
51:869-877; Slack et al. (1987)
Nature
326:197-200; Kimelman et al. (1988)
Science
242:1053-1056; Amaya et al. (1991)
Cell
66:257-270).
The FGFs mediate their effects by binding to high affinity cell surface receptors (reviewed in Johnson and Williams (1992)
Adv. Cancer Res.
60:1-41). Four distinct FGF receptors have been identified: FGFR1 (also known was Flg, bFGFR, Cek1 or N-bFGFR) (Lee et al. (1989)
Science
245:57-60; Dionne et al. (1990)
EMBO J.
9:2685-2692; Johnson et al. (1990)
Mol. Cell. Biol.
10:4728-4736; Eisemann et al. (1991)
Oncogene
6:1195-1202; Hou et al. (1991)
Science
251:665-668), FGFR2 (also known as Bek, Cek3, K-sam, TK14, TK25 or KGFR) (Dionne et al. (1990)
EMBO J.
9:2685-2692; Hattori et al. (1990)
Proc. Natl. Acad. Sci. USA
87:5983-5987; Miki et al. (1991)
Science
251:72-75; Saiki et al. (1988)
Science
239:487-491; Pasquale (1990)
Proc. Natl. Acad. Sci. USA
87:5812-5816; Houssaint et al. (1990)
Proc. Natl. Acad. Sci. USA
87:8180-8184; Champion-Arnaud et al. (1991)
Oncogene
6:979-987; Crumley et al. (1991)
Oncogene
6:2255-2262; Raz et al. (1991)
Oncogene
6:753-760; Sato et al. (1991)
Oncogene
6:1279-1283), FGFR3 (also known as Cek2) (Keegan et al. (1991)
Proc. Natl. Acad. Sci. USA
88:1095-1099) and FGFR4 (Partanen et al. (1991)
EMBO J.
10:1347-1354).
Structurally, the FGF receptors comprise an amino terminal signal peptide, three extracellular immunoglobulin-like domains (Ig domain I, Ig domain II, Ig domain III), with an acidic region between Ig domains I and II (the “acidic box” domain), a transmembrane region, and intracellular kinase domains (Johnson and Williams (1992)
Adv. Cancer Res.
60:1-41). Variant forms of FGF receptors are generated by alternative mRNA splicing (Champion-Arnaud et al. (1991)
Oncogene
6:979-987; Johnson et al. (1991)
Mol. Cell. Biol.
11:4627-4634; Johnson and Williams (1992)
Adv. Cancer Res.
60:1-41). Binding studies have demonstrated that multiple members of the FGF family can bind to the same receptor species (Dionne et al. (1990)
EMBO J.
9:2685-2692; Johnson et al. (1990)
Mol. Cell. Biol.
10:4728-4736; Mansukhani et al. (1990)
Proc. Natl. Acad. Sci. USA
87:4378-4382; Keegan et al. (1991)
Proc. Natl. Acad. Sci. USA
88:1095-1099). Alternative splice variants, particularly involving Ig domain III, are thought to be important in determining the ligand binding specificity of receptor species (Werner (1992)
Mol. Cell. Biol.
12:82-88; Crumley et al. (1991)
Oncogene
6:2255-2262). Moreover, analogous splice variants from different FGFR genes have been shown to encode receptor forms with different ligand binding specificities (Dionne et al. (1990)
EMBO J.
9:2685-2692; Johnson et al. (1990)
Mol. Cell. Biol.
10:4728-4736; Mansukhani et al. (1990)
Proc. Natl. Acad. Sci. USA
87:4378-4382).
Given the role of FGF family members in a variety of biological processes, compounds that modulate FGF receptor activity would be advantageous. Certain retro-peptides have been described as FGF receptor blocking peptides (PCT Publication No. WO 92/13958). Moreover, soluble forms of FGF receptors, comprising the extracellular domains, have been described (U.S. Pat. No. 5,288,855 by Bergonzoni et al.; PCT Publication No. WO 91/00916; PCT Publication WO 92/00999; European Patent 529 076 B1). Additional compounds for modulating FGF receptor activity are still needed.
SUMMARY OF THE INVENTION
This invention pertains to peptide compounds, pharmaceutical compositions comprising these peptide compounds and methods of using these peptide compounds. The peptide compounds of the invention bind either a fibroblast growth factor (FGF) or a fibroblast growth factor receptor (FGFR) (preferably, FGFR2-IIIC). Accordingly, the peptide compounds of the invention are useful as modulators of FGFR activity. A peptide compound of the invention may be an agonist or an antagonist of FGFR activity.
In a preferred embodiment, a peptide compound of the invention is based on the consensus amino acid sequence: (Y/F)-(L/F/I)-(R/D/E/S/Y/G)-(Q/L/Y)-Y-(M/L/K/R)-(L/M/D/E/N/S)-(R/L/S/T)-(L/F/M/V) (SEQ ID NO: 1). Accordingly, a peptide compound of the invention can comprise an amino acid sequence:
Y
1
-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Y
2
wherein:
Y
1
is hydrogen, an amino-derivative group or a peptidic structure having a formula (Xaa)
a
wherein Xaa is any amino acid structure and a is an integer from 1-15 inclusive;
Y
2
is hydrogen, a carboxy-derivative group or a peptidic structure having a formula (Xaa)
b
wherein Xaa is any amino acid structure and b is an integer from 1-15 inclusive;
Xaa1 is a tyrosine structure or a phenylalanine structure;
Xaa2 is a leucine structure, a phenylalanine structure or isoleucine structure;
Xaa3 is an arginine structure, an aspartic acid structure, a glutamic acid structure, a serine structure, a tyrosine structure or a glutamine structure;
Xaa4 is glutamine structure, a leucine structure or a tyrosine structure;
Xaa5 is a tyrosine structure;
Xaa6 is a methionine structure, a leucine structure, a lysine structure or an arginine structure;
Xaa7 is a leucine structure, a methionine structure, an aspartic acid structure, a glutamic acid structure, an asparagine structure or a serine structure;
Xaa8 is an arginine structure, a leucine structure, a serine structure or a threonine structure; and
Xaa9 is leucine, phenylalanine structure, a methionine structure or a valine structure.
The peptide compounds of the invention can be formulated into pharmaceutical compositions, preferably comprising a peptide compound and a pharmaceutically acceptable carrier.
The peptide compounds of the invention can be used to modulate FGFR activity in a cell by contacting a cell expressing the FGFR with the peptide compound such that FGFR activity in the cell is modulated. In the modulatory methods of the invention, the peptide compound can b

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