# US 6,723,694 B1 · Short peptides which selectively modulate intracellular signalling

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- Number: US 6,723,694 B1
- Document ID: US6723694B1
- Status: Granted
- Kind: B1
- Application number: 08/861,153
- Filed: 1997-05-21
- Granted: 2004-04-20
- Earliest claimed: 1997-05-21
- Assignees: Children's Medical Center Corporation; Yissum Research Development Company of the Hebrew University of Jerusalem
- Inventors: Shmuel A. Ben-Sasson
- Web page: https://patentgrep.com/patent/US6723694B1

## CPC

- A61K 38/45: Transferases (2)
- A61P 9/02: Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 17/06: Antipsoriatics
- A61P 35/00: Antineoplastic agents
- C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

Disclosed are peptides which are peptide derivatives of the HJ loop of a protein tyrosine kinase. The peptides can modulate the activity of the protein tyrosine kinase. Also disclosed are methods of modulating the activity of a protein tyrosine kinase in a subject by administering one of the peptides of the present invention.

## Claims

### Claim 1

A peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
(a) a subsequence of an HJ-loop peptide, which subsequence consists of at least five contiguous amino acids of said HJ-loop peptide, and which subsequence peptide modulates the activity of the protein tyrosine kinase of which said HJ-loop peptide is a part, wherein said HJ-loop peptide is a peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
(b) a modified sequence peptide having a modified sequence of (a) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
(c) a protected peptide (a) or (b) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase; or
(d) a cyclized peptide of (a), (b), or (c) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.

### Claim 2 (depends on 1)

A peptide in accordance with claim 1, consisting of a subsequence peptide of (a); a peptide of (a) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase; or a peptide of (a) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.

### Claim 3 (depends on 2)

A peptide in accordance with claim 2, consisting of a subsequence peptide of (a).

### Claim 4 (depends on 1)

A peptide in accordance with claim 1, consisting of a modified sequence peptide of (b); a peptide of (b) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase; or a peptide of (b) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.

### Claim 5 (depends on 4)

A peptide in accordance with claim 4, consisting of a modified peptide of (b).

### Claim 6 (depends on 1)

A peptide in accordance with claim 1, consisting of a protected peptide of (c).

### Claim 7 (depends on 6)

A peptide in accordance with claim 6, consisting of a cyclized peptide of (d).

### Claim 8 (depends on 6)

The peptide of claim 6, wherein the N-terminal amino acid is amidated and the C-terminal amino acid is acylated.

### Claim 9 (depends on 1)

The peptide of claim 1, wherein the protein tyrosine kinase is a member of a protein tyrosine kinase family selected from the group consisting of Src, EGF-R, FGF-R, VEGF-R, HGF-R, PDGF-R, insulin receptor family and neurotrophin receptor family.

### Claim 10 (depends on 9)

The peptide of claim 9, wherein the protein tyrosine kinase is from the src family of protein tyrosine kinases and is selected from the group consisting of c-Src, c-Yes, FYN, FGR, HCK, LYN, LCK and BLK.

### Claim 11 (depends on 1)

The peptide of claim 1, wherein the protein tyrosine kinase is selected from group of protein tyrosine kinases consisting of RET, CSK, c-Met, c-Abl and FAK.

### Claim 12 (depends on 1)

The peptide of claim 1, wherein the peptide is a heptapeptide.

### Claim 13 (depends on 12)

The peptide of claim 12, wherein the peptide consists of the sequence Leu-Val-Thr-Xaa-Gly-Arg-Val (SEQ ID NO.: 45), wherein Xaa is selected from the group consisting of L-lysine, D-lysine, histidine, tyrosine, phenylalanine and arginine.

### Claim 14 (depends on 12)

The peptide of claim 12, wherein the peptide consists of the sequence Gly-Arg-Val-Pro-Yaa-Pro-Zaa (SEQ ID NO.: 46), wherein:
(a) Yaa is selected from the group consisting of tyrosine, phenylalanine and tryptophane; and
(b) Zaa is selected from the group consisting of glycine, alanine and arginine.

### Claim 15 (depends on 9)

The peptide of claim 9, wherein the protein tyrosine kinase is from the EGF-R family of protein tyrosine kinases and is selected from the group consisting of EGFR, ErbB2, ErbB3 and ErB4.

### Claim 16 (depends on 9)

The peptide of claim 9, wherein the protein tyrosine kinase is from the FGF-R family of protein tyrosine kinases and is selected from the group consisting of FGFR1, FGFR2, FGFR3 and FGFR4.

### Claim 17 (depends on 9)

The peptide of claim 9, wherein the protein tyrosine kinase is from the VEGF-R family of protein tyrosine kinases and is selected from the group consisting of Flt1, Flt4 and Flk1.

### Claim 18 (depends on 9)

The peptide of claim 9, wherein the protein tyrosine kinase is from the insulin receptor family of protein tyrosine kinases and is selected from the group consisting of INS-R, IRR and IGF1-R.

### Claim 19 (depends on 9)

The peptide of claim 9, wherein the a protein tyrosine kinase is from the neurotrophin receptor family of protein tyrosine kinases and is selected from the group consisting of TrkA, TrkB and TrkC.

### Claim 20 (depends on 1)

The peptide of claim 1, wherein the peptide has a sequence selected from the group of peptides consisting of HJ4 (SEQ ID NO.: 13), HJ4.2 (SEQ ID NO.: 14), HJ4Nitro (SEQ ID NO.: 15), HJ6 (SEQ ID NO.: 16), HJ7 (SEQ ID NO.: 17), HJ7.1 (SEQ ID NO.: 18), HJ8 (SEQ ID NO.: 19), HJ9 (SEQ ID NO.: 20), HJ10 (SEQ ID NO.: 21), HJ11 (SEQ ID NO.: 22), HJ11.1 (SEQ ID NO.: 23), HJ11Met (SEQ ID NO.: 24), HJ12 (SEQ ID NO.: 25), HJ13 (SEQ ID NO.: 26), HJ14 (SEQ ID NO.: 27), HJ15 (SEQ ID. NO.: 28), HJ18 (SEQ ID NO.: 29), HJ20, (SEQ ID NO.: 30), HJ20.1 (SEQ ID NO.: 31), HJ21.1 (SEQ ID NO.: 32), HJ22 (SEQ ID NO.: 33), HJ23.1 (SEQ ID NO.: 34), HJ24 (SEQ ID NO.: 1), HJ25 (SEQ ID NO.: 35), HJ27 (SEQ ID NO.: 36), HJ28 (SEQ ID NO.: 37), HJ29 (SEQ ID NO.: 48), HJ30 (SEQ ID NO.: 38), HJ31 (SEQ ID NO.: 39), HJ32 (SEQ ID NO.: 2), HJ33 (SEQ ID NO.: 40), HJ34 (SEQ ID NO.: 41), HJ40 (SEQ ID NO.: 47), Lena 1 (SEQ ID NO.: 42), Lena 2 (SEQ ID NO.: 43) and J29 (SEQ ID NO.: 44).

### Claim 21

A peptide having the sequence of a peptide selected from the group consisting of HJ4 (SEQ ID NO.: 13), HJ4.2 (SEQ ID NO.: 14), HJ4Nitro (SEQ ID NO.: 15), HJ6 (SEQ ID NO.: 16), HJ7 (SEQ ID NO.: 17), HJ7.1 (SEQ ID NO.: 18), HJ8 (SEQ ID NO.: 19), HJ9 (SEQ ID NO.: 20), HJ10 (SEQ ID NO.: 21), HJ11 (SEQ ID NO.: 22), HJ11.1 (SEQ ID NO.: 23), HJ11Met (SEQ ID NO.: 24), HJ12 (SEQ ID NO.: 25), HJ13 (SEQ ID NO.: 26), HJ14 (SEQ ID NO.: 27), HJ15 (SEQ ID NO.: 28), HJ18 (SEQ ID NO.: 29), HJ20, (SEQ ID NO.: 30), HJ20.1 (SEQ ID NO.: 31), HJ21.1 (SEQ ID NO.: 32), HJ22 (SEQ ID NO.: 33), HJ23.1 (SEQ ID NO.: 34), HJ24 (SEQ ID NO.: 1), HJ25 (SEQ ID NO.: 35), HJ27 (SEQ ID NO.: 36), HJ28 (SEQ ID NO.: 37), HJ29 (SEQ ID NO.: 48), HJ30 (SEQ ID NO.: 38), HJ31 (SEQ ID NO.: 39), HJ32 (SEQ ID NO.: 2), HJ33 (SEQ ID NO.: 40), HJ34 (SEQ ID NO.: 41), HJ40 (SEQ ID NO.: 47), Lena 1 (SEQ ID NO.: 42), Lena 2 (SEQ ID NO.: 43) and J29 (SEQ ID NO.: 44), with the proviso that any one amino acid residue in the peptide can be substituted by another amino acid residue or amino acid residue analog.

### Claim 22

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is threonine or tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA4 is selected from the group consisting of methionine, threonine, serine, valine, isoleucine and leucine;
AA5 is threonine or serine;
AA6 is selected from the group consisting of ornithine, lysine, histidine, tyrosine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA7 is glycine or alanine;
AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid and lysine;
AA9 is selected from the group consisting of valine, isoleucine, leucine and methionine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is proline;
AA13 is glycine or alanine;
AA14 is selected from the group consisting of methionine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA15 is selected from the group consisting of valine, asparagine, threonine and serine;
AA16 is asparagine or lysine;
AA17 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid alanine, and proline;
AA18 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.

### Claim 23 (depends on 22)

The peptide of claim 22, wherein said sequence is that of SEQ ID NO:3 or SEQ ID NO:4, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 22.

### Claim 24 (depends on 22)

The peptide of claim 22, wherein said sequence is that of SEQ ID NO:3, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 22.

### Claim 25 (depends on 23, 24)

The peptide of claim 23 or claim 24, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 26

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benxyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of valine, leucine, isoleucine and methionine;
AA4 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA5 is threonine or serine;
AA6 is tyrosine, phenylalanine or tryptophan;
AA7 is glycine or alanine;
AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid, ornithine, and lysine;
AA9 is valine or alanine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is proline;
AA13 is selected from the group consisting of ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid and lysine;
AA14 is selected from the group consisting of valine, methionine, isoleucine and leucine;
AA15 is selected from the group consisting of proline, threonine and serine;
AA16 is selected from the group consisting of leucine, isoleucine, valine and methionine;
AA17 is selected from the group consisting of ornithine, lysine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyargine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA18 is selected from the group consisting of asparagine, glutamine, glutamic acid, aspartic acid, and an aliphatic, substituted aliphatic, benzyl, substituted benzyl or substituted aromatic ester of aspartic acid or glutamic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.

### Claim 27 (depends on 26)

The peptide of claim 26, wherein said sequence is that of SEQ ID NO:5, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 26.

### Claim 28 (depends on 26)

The peptide of claim 26, wherein said sequence is that of SEQ ID NO:5, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 26.

### Claim 29 (depends on 27, 28)

The peptide of claim 27 or claim 28, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 30

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is glutamic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or aromatic ester of glutamic acid;
AA3 is selected from the group consisting of isoleucine, leucine, alanine and methionine;
AA4 is selected from the group consisting of alanine, glycine and valine;
AA5 is threonine or serine;
AA6 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA7 is glycine or alanine;
AA8 is selected from the group consisting of methionine, valine, leucine and isoleucine;
AA9 is serine or threonine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is proline;
AA13 is glycine or alanine;
AA14 is selected from the group consisting of methionine, isoleucine, valine and leucine;
AA15 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA16 is selected from the group consisting of leucine, isoleucine, proline, lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA17 is serine or threonine;
AA18 is selected from the group consisting of glutamine, asparagine, glutamicacid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of tyrosine, phenylalanine and tryptophan.

### Claim 31 (depends on 30)

The peptide of claim 30, wherein said, sequence is that of SEQ ID NO:6, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 30.

### Claim 32 (depends on 30)

The peptide of claim 30, wherein said sequence is that of SEQ ID NO:6, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 30.

### Claim 33 (depends on 31, 32)

The peptide of claim 31 or claim 32, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 34

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, valine and methionine;
AA4 is selected from the group consisting of methionine, leucine, isoleucine and valine;
AA5 is threonine or serine;
AA6 is selected from the group consisting of tyrosine, lysine, arginine, ornithine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA7 is glycine or alanine;
AA8 is glycine or alanine;
AA9 is selected from the group consisting of proline, serine and threonine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is proline;
AA13 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA14 is selected from the group consisting of valine, methionine, isoleucine and leucine;
AA15 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA16 is threonine or proline;
AA17 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of threonine, serine and C-agitated derivatives thereof.

### Claim 35 (depends on 34)

The peptide of claim 34, wherein said sequence is that of SEQ ID NO:7, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof c an each vary among the variations specified for such residue in claim 34.

### Claim 36 (depends on 34)

The peptide of claim 34, wherein said sequence is that of SEQ ID NO:7, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof m ay vary among the variations specified for such residue in claim 34.

### Claim 37 (depends on 35, 36)

The peptide of claim 35 or claim 36, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 38

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA4 is selected from the group consisting of methionine, leucine, isoleucine and valine;
AA5 is selected from the group consisting of methionine, valine, isoleucine and leucine;
AA6 is selected from the group consisting of histidine, lysine and ornithine;
AA7 is glycine or alanine;
AA8 is selected from the group consisting of valine, alanine and glycine;
AA9 is selected from the group consisting of lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is glutamine or proline;
AA13 is glycine or alanine;
AA14 is selected from the group consisting of valine, isoleucine, leucine and alanine;
AA15 is selected from the group consisting of lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA16 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA17 is selected from the group consisting of glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of aspartic acid and glutamic acid;
AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of valine, isoleucine, leucine, methionine and C-agitated derivatives thereof.

### Claim 39 (depends on 38)

The peptide of claim 38, wherein said sequence is that of SEQ ID NO:8, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 38.

### Claim 40 (depends on 38)

The peptide of claim 38, wherein said siquence is that of SEQ ID NO:8, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 38.

### Claim 41 (depends on 39, 40)

The peptide of claim 39 or claim 40, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 42

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan or methionine;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA4 is selected from the group consisting of methionine, valine, isoleucine and leucine;
AA5 is threonine or serine;
AA6 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
AA7 is glycine or alanine;
AA8 is selected from the group consisting of arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline, 2-amino-4-guanidinobutanoic acid, lysine and ornithine;
AA9 is selected from the group consisting of valine, isoleucine, leucine and methionine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is proline;
AA13 is glycine or alanine;
AA14 is selected from the group consisting of methionine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine , N-amidinocitruline and 2-amino-4-guanidinobutanoic acid;
AA15 is threonine or serine;
AA16 is asparagine or glutamine;
AA17 is selected from the group consisting of alanine, glycine and proline;
AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of valine, isoleucine, leucine and methionine; and
AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.

### Claim 43 (depends on 42)

The peptide of claim 42, wherein said sequence is that of SEQ ID NO:9, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 42.

### Claim 44 (depends on 42)

The peptide of claim 42, wherein said sequence is that of SEQ ID NO:9, or a subsequence thereof comprisign at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 42.

### Claim 45 (depends on 43, 44)

The peptide of claim 43 or claim 44, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 46

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA4 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
AA5 is threonine or serine;
AA6 is selected from the group consisting of leucine, isoleucine, valine and methionine;
AA7 is glycine or alanine;
AA8 is glycine or alanine;
AA9 is serine or threonine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is selected from the group consisting of proline, cysteine, serine and alanine;
AA13 is glycine or alanine;
AA14 is selected from the group consisting of rmethionine, valine, isoleucine and leucine;
AA15 is selected from the group consisting of serine, threonine, methionine, proline, lysine, ornithine, glutamine and asparagine;
AA16 is selected from the group consisting of cysteine, serine, methionine, valine, isoleucine and leucine;
AA17 is selected from the group consisting of alanine, asparagine, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of aspartic acid;
AA18 is selected from the group consisting of threonine, serine, glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of threonine, leucine, glutamine, asparagine, glutamic acid, aspartic acid and an aliphatic substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid; and
AA20 is selected from the group consisting of tyrosine, phenylalanine and tryptophan.

### Claim 47 (depends on 46)

The peptide of claim 46, wherein said sequence is that of SEQ ID NO:10, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 the subsequence thereof can each vary among the variations specified for such residue in claim 46.

### Claim 48 (depends on 46)

The peptide of claim 46, wherein said sepuence is that of SEQ ID NO:10, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 46.

### Claim 49 (depends on 47, 48)

The peptide of claim 47 or claim 48, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 50

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is tryptophan;
AA2 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA3 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA4 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
AA5 is threonine or serine;
AA6 is selected from the group consisting of phenylalanine, tyrosine and tryptophan;
AA7 is glycine or alanine;
AA8 is lsyine or ornithine;
AA9 is glutamine or asparagine;
AA10 is proline;
AA11 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA12 is selected from the group consisting of tyrosine, phenylalanine and tryptophan;
AA13 is glutamine or asparagine;
AA14 is selected from the group consisting of leucine, isoleucine, methionine and valine;
AA15 is serine or threonine;
AA16 is glutamine or asparagine;
AA17 is threonine or asparagine;
AA18 is selected from the group consisting of glutamic acid, aspartic acid and an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA19 is selected from the group consisting of glycine, alanine and valine; and
AA20 is selected from the group consisting of leucine, isoleucine, methionine and valine.

### Claim 51 (depends on 50)

The peptide of claim 50, wherein said sequence is that of SEQ ID NO:11, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 50.

### Claim 52 (depends on 50)

The peptide of claim 50, wherein said sequence is that of SEQ ID NO:11, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 50.

### Claim 53 (depends on 51, 52)

The peptide of claim 51 or claim 52, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 54

A peptide consisting of a sequence of amino acids AA1 through AA20, or a subsequence thereof consisting of at least five contiguous amino acids thereof, wherein:
AA1 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA2 is leucine, isoleucine, methionine or valine;
AA3 is serine, threonine or proline;
AA4 is phenylalanine, tyrosine or tryptophan;
AA5 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted-benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA6 is leucine, isoleucine, methionine or valine;
AA7 is leucine, isoleucine, methionine or valine;
AA8 is threonine or serine;
AA9 is phenylalanine, tyrosine or tryptophan;
AA10 is glycine or alanine;
AA11 is serine, alanine, threonine or glycine;
AA12 is lysine, ornithine, arginine, N-nitroarginine, β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline or 2-amino-4-guanidinobutanoic acid;
AA13 is proline;
AA14 is tyrosine, phenylalanine or tryptophan;
AA15 is glutamic acid, aspartic acid or an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aromatic or substituted aromatic ester of glutamic acid or aspartic acid;
AA16 is glycine or alanine;
AA17 is leucine, isoleucine, methionine or valine;
AA18 is proline;
AA19 is glycine, alanine, serine or threonine; and
AA20 is serine, arginine, N-nitroarginine β-cycloarginine, γ-hydroxyarginine, N-amidinocitruline or 2-amino-4-guanidinobutanoic acid.

### Claim 55 (depends on 54)

The peptide of claim 54, wherein said sequence is that of SEQ ID NO:12, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that up to two amino acids in the sequence AA1 through AA20 or the subsequence thereof can each vary among the variations specified for such residue in claim 54.

### Claim 56 (depends on 54)

The peptide of claim 54, wherein said sequence is that of SEQ ID NO:12, or a subsequence thereof comprising at least five contiguous amino acids thereof, with the proviso that any one amino acid in the sequence AA1 through AA20 or the subsequence thereof may vary among the variations specified for such residue in claim 54.

### Claim 57 (depends on 55, 56)

The peptide of claim 55 or claim 56, wherein the peptide comprises an eight amino acid subsequence selected from the group consisting of AA3 through AA10, AA7 through AA14 and AA11 through AA18.

### Claim 58

A protected or cyclized peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
(a) an HJ-loop peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
(b) a subsequence peptide consisting of a subsequence of (a) consisting of at least five contiguous amino acids thereof, which subsequence peptide modulates the activity of the protein tyrosine kinase; or
(c) a modified sequence peptide having a modified sequence of (a) or (b) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
which peptide of (a), (b) or (c) is (1) a protected peptide in which the N-terminus and/or the C-terminus is protected by a protecting group which facilitates transport of the peptide into a cell, which protected peptide modulates the activity of the protein tyrosine kinase, or
which peptide of (a), (b) or (c) or said protected peptide is (2) a cyclized peptide in which said peptide of (a), (b) or (c) or said protected peptide has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.

### Claim 59 (depends on 58)

A protected or cyclized peptide in accordance with claim 58, consisting of said protected peptide of (1).

### Claim 60 (depends on 58)

A protected or cyclized peptide in accordance with claim 58, consisting of said cyclized peptide of (2).

### Claim 61 (depends on 58)

A protected or cyclized peptide in accordance with claim 58, wherein said peptide which is protected or cyclized consists of an HJ-loop peptide of (a).

### Claim 62 (depends on 59)

A protected peptide in accordance with claim 59, wherein said peptide which is protected consists of an HJ-loop peptide of (a).

### Claim 63 (depends on 60)

A cyclized peptide in accordance with claim 60, wherein said peptide which is cyclized consists of an HJ-loop peptide of (a).

### Claim 64 (depends on 58)

A protected or cyclized peptide in accordance with claim 58, wherein said peptide which is protected or cyclized consists of a subsequence peptide of (b).

### Claim 65 (depends on 59)

A protected peptide in accordance with claim 59, wherein said peptide which is protected consists of subsequence peptide of (b).

### Claim 66

A cyclized peptide in accordance with cliam 60, wherein said peptide which is cyclized consists of a subsequence peptide of (b).

### Claim 67 (depends on 58)

A protected or cyclized peptide in accordance with claim 58, wherein said peptide which is protected or cyclized consists of a modified sequence peptide of (c).

### Claim 68 (depends on 59)

A protected peptide in accordance with claim 59, wherein said peptide which is protected consists of a modified sequence peptide of (c).

### Claim 69 (depends on 60)

A cyclized peptide in accordance with claim 60, wherein said peptide which is cyclized consists of a modified sequence peptide of (c).

### Claim 70 (depends on 59)

The protected or cyclized peptide of claim 59, wherein the N-terminal amino acid is amidated and the C-terminal amino acid is acylated.

### Claim 71 (depends on 1)

The protected or cyclized peptide of claim 1, wherein the protein tyrosine kinase is a member of a protein tyrosine kinase familyselected from the group consisting of Src, EGF-R, FGF-R, VEGF-R, HGF-R, PDGF-R, insulin receptor family and neurotrophin receptor family.

### Claim 72 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the src family of protein tyrosine kinases and is selected from the group consisting of c-Src, c-Yes, FYN, FGR, HCK, LYN, LCK and BLK.

### Claim 73 (depends on 58)

The protected or cyclized peptide of claim 58, wherein the protein tyrosine kinase is selected from group of protein tyrosine kinases consisting of RET, CSK, c-Met, c-Abl and FAK.

### Claim 74 (depends on 64)

The protected or cyclized peptide of claim 64, wherein the subsequence peptide of (b) is a heptapeptide.

### Claim 75 (depends on 74)

The protected or cyclized peptide of claim 74 , wherein the subsequence peptide of (b) consists of the sequence Leu-Val-Thr-Xaa-Gly-Arg-Val (SEQ ID NO.: 45), wherein Xaa is selected from the group consisting of L-lysine, D-lysine, histidine, tyrosine, phenylalanine and arginine.

### Claim 76 (depends on 74)

The protected or cyclized peptide of claim 74, wherein the subsequence peptide of (b) consists of the sequence Gly-Arg-Val-Pro-Yaa-Pro-Zaa (SEQ ID NO.: 46), wherein:
(a) Yaa is selected from the group consisting of tyrosine, phenylalanine and tryptophane; and
(b) Zaa is selected from the group consisting of glycine, alanine and arginine.

### Claim 77 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the EGF-R family of protein tyrosine kinases and is selected from the group consisting of EGFR, ErbB2, ErbB3 and ErB4.

### Claim 78 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the FGF-R family of protein tyrosine kinases and is selected from the group consisting of FGFR1, FGFR2, FGFR3 and FGFR4.

### Claim 79 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the VEGF-R family of protein tyrosine kinases and is selected from the group consisting of Flt1, Flt4 and Flk1.

### Claim 80 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the insulin receptor family of protein tyrosine kinases and is selected from the group consisting of INS-R, IRR and IGF1-R.

### Claim 81 (depends on 71)

The protected or cyclized peptide of claim 71, wherein the protein tyrosine kinase is from the neurotrophin receptor family of protein tyrosine kinases and is selected from the group consisting of TrkA, TrkB and TrkC.

### Claim 82 (depends on 58)

The protected or cyclized peptide of claim 58, wherein the peptide has a sequence selected from the group of peptides consisting of HJ4 (SEQ ID NO.: 13), HJ4.2 (SEQ ID NO.: 14), HJ4Nitro (SEQ ID NO.: 15), HJ6 (SEQ ID NO.: 16), HJ7 (SEQ ID NO.: 17), HJ7.1 (SEQ ID NO.: 18), HJ8 (SEQ ID NO.: 19), HJ9 (SEQ ID NO.: 20), HJ10 (SEQ ID NO.: 21), HJ11 (SEQ ID NO.: 22), HJ11.1 (SEQ ID NO.: 23), HJllMet (SEQ ID NO.: 24), HJ12 (SEQ ID NO.: 25), HJ13 (SEQ ID NO.: 26), HJ14 (SEQ ID NO.: 27), HJ15 (SEQ ID NO.: 28), HJ18 (SEQ ID NO.: 29), HJ20, (SEQ ID NO.: 30), HJ20.1 (SEQ ID NO.: 31), HJ21.1 (SEQ ID NO.: 32), HJ22 (SEQ ID NO.: 33), HJ23.1 (SEQ ID NO.: 34), HJ24 (SEQ ID NO.: 1), HJ25 (SEQ ID NO.: 35), HJ27 (SEQ ID NO.: 36), HJ28 (SEQ ID NO.: 37), HJ29 (SEQ ID NO.: 48), HJ30 (SEQ ID NO.: 38), HJ31 (SEQ ID NO.: 39), HJ32 (SEQ ID NO.: 2), HJ33 (SEQ ID NO.: 40), HJ34 (SEQ ID NO.: 41), HJ40 (SEQ ID NO.: 47), Lena 1 (SEQ ID NO.: 42), Lena 2 (SEQ ID NO.: 43) and J29 (SEQ ID-NO.: 44), or has a sequence which is that of one of said-peptides which has been modified wherein any one amino acid residue in the peptide is substituted by another amino acid residue or amino acid residue analog, which modified peptide modulates the activity of the protein tyrosine kinase.

### Claim 83 (depends on 82)

The protected or cyclized peptide of claim 82, wherein the peptide of (a), (b) or (c) has a sequence selected from the group of peptides consisting of HJ4 (SEQ ID NO.: 13), HJ4.2 (SEQ ID NO.: 14), HJ4Nitro (SEQ ID NO.: 15), HJ6 (SEQ ID NO.: 16), HJ7 (SEQ ID NO.: 17), HJ7.1 (SEQ ID NO.: 18), HJ8 (SEQ ID NO.: 19), HJ9 (SEQ ID NO.: 20), HJ10 (SEQ ID NO.: 21), HJ11 (SEQ ID NO.: 22), HJ11.1 (SEQ ID NO.: 23), HJllMet (SEQ ID NO.: 24), HJ12 (SEQ ID NO.: 25), HJ13 (SEQ ID NO.: 26), HJ14 (SEQ ID NO.: 27), HJ15 (SEQ ID NO.: 28), HJ18 (SEQ ID NO.: 29), HJ20, (SEQ ID NO.: 30), HJ20.1 (SEQ ID NO.: 31), HJ21.1 (SEQ ID NO.: 32), HJ22 (SEQ ID NO.: 33), HJ23.1 (SEQ ID NO.: 34), HJ24 (SEQ ID NO.: 1), HJ25 (SEQ ID NO.: 35), HJ27 (SEQ ID NO.: 36), HJ28 (SEQ ID NO.: 37), HJ29 (SEQ ID NO.: 48), HJ30 (SEQ ID NO.: 38), HJ31 (SEQ ID NO.: 39), HJ32 (SEQ ID NO.: 2), HJ33 (SEQ ID NO.: 40), HJ34 (SEQ ID NO.: 41), HJ40 (SEQ ID NO.: 47), Lena 1 (SEQ ID NO.: 42), Lena 2 (SEQ ID NO.: 43) and J29 (SEQ ID NO.: 44).

### Claim 84 (depends on 6)

A peptide in accordance with claim 6, wherein said protecting group is a group which facilitates transport of the peptide into a cell.

### Claim 85

A method of modulating activity of a protein tyrosine kinase in a subject, comprising administering a therapeutically effective amount of a peptide capable of modulating the activity of a protein tyrosine kinase having a structure that includes the twelve subdomains and nine alpha helices that are characteristic of the protein tyrosine kinase superfamily, consisting of:
(a) an HJ-loop peptide consisting of a sequence of about 20 amino acid residues of the protein tyrosine kinase between the middle of Subdomain IX and the middle of Subdomain X, beginning about five residues from the N-terminus of the F helix and extending to about five amino acid residues into the G helix, which amino acids correspond to a continuous stretch of the prototypical PKA-Cα in positions 229-248 of the PKA-Cα, and which HJ-loop peptide modulates the activity of the protein tyrosine kinase;
(b) a subsequence peptide consisting of a subsequence of (a) consisting of at least five contiguous amino acids thereof, which subsequence peptide modulates the activity of the protein tyrosine kinase;
(c) a modified sequence peptide having a modified sequence of (a) or (b) in which up to two residues are each substituted by another amino acid residue or amino acid residue analog, which modified sequence peptide modulates the activity of the protein tyrosine kinase;
(d) a protected peptide (a), (b) or (c) in which the N-terminus and/or the C-terminus is protected by a protecting group, which protected peptide modulates the activity of the protein tyrosine kinase; or
(e) a cyclized peptide of (a), (b), (c) or (d) which has been cyclized, which cyclized peptide modulates the activity of the protein tyrosine kinase.

### Claim 86 (depends on 58)

A method of modulating activity of a protein tyrosine kinase in a subject, comprising administering a therapeutically effective amount of a protected or cyclized peptide in accordance with claim 58.

### Claim 87 (depends on 1)

A method of modulating activity of a protein tyrosine kinase in a subject, comprising administering a therapeutically effective amount of a peptide in accordance with claim 1.