Cyclic peptides that bind to urokinase-type plasminogen activator receptor
OwnerTerence R. Jones, David N. Haney +1inventors
InventorsTerence R. Jones, David N. Haney, Janos Varga
Life of this patent
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Abstract
Cyclic peptide compounds having 11 amino acids joined by a linking unit L, such that the linear dimension between the Cα carbon of the first amino acid and the Cα carbon of eleventh amino acid is between about 4 and 12 Ångstrom units; are useful for inhibiting the binding of uPA to the uPAR receptor.: Methods for using the cyclic peptide compounds, and compositions containing them, for inhibiting the growth or metastasis of cancerous tumors are also disclosed.
Claims32
A cyclic peptide compound of Formula 1 or Formula 2
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- wherein, in Formula 1, all of X1 through X11 represent L-series amino acids and, in Formula 2, all of X1 through X11 represent D-series amino acids;
- X1 is Val, Pro, or Ala;
- X2 is Ser or Ala;
- X3 is Asn or Gln;
- X4 is Lys or His;
- X5 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalamine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X6 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X7 is Ser or Ala;
- X8 is Asn or Ala;
- X9 is Ile, Leu, or Val;
- X10 is His or Ala;
- X11 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- and
- L is a linking unit, such that when X1 and X11 are linked, the linear dimension between the Cα carbon of amino acid X1 and the Cα carbon of amino acid X11 is between about 4 and 12 Ångstrom units;
- with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond.
A method for inhibiting the binding of uPA to uPAR, said method comprising the step of contacting living cells with a cyclic peptide compound of Formula 1 or Formula 2
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- wherein, in Formula 1, all of X1 through X11 represent L-series amino acids and, in Formula 2, all of X1 through X11 represent D-series amino acids;
- X1 is Val, Pro, or Ala;
- X2 is Ser or Ala;
- X3 is Asn or Gln;
- X4 is Lys or His;
- X5 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X6 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X7 is Ser or Ala;
- X8 is Asn or Ala;
- X9 is Ile, Leu, or Val;
- X10 is His or Ala;
- X11 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
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- L is a linking unit, such that when X1 and X11 are linked, the linear dimension between the Cα carbon of amino acid X1 and the Cα carbon of amino acid X11 is between about 4 and 12 Ångstrom units;
- with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond.
A pharmaceutical composition comprising (a) the cyclic peptide compound of Formula 1 or Formula 2
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- wherein, in Formula 1, all of X1 through X11 represent L-series amino acids and, in Formula 2, all of X1 through X11 represent D-series amino acids;
- X1 is Val, Pro, or Ala;
- X2 is Ser or Ala;
- X3 is Asn or Gln;
- X4 is Lys or His;
- X5 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X6 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- X7 is Ser or Ala;
- X8 is Asn or Ala;
- X9 is Ile, Leu, or Val;
- X10 is His or Ala;
- X11 is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;
- and
- L is a linking unit, such that when X1 and X11 are linked, the linear dimension between the Cα carbon of amino acid X1 and the Cα carbon of amino acid X11 is between about 4 and 12 Ångstrom units;
- with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond;
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- (b) a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.