COMPLEX-FORMATION-MODULATING AGENTS AND USES THEREFOR

摘要

Disclosed are methods and agents for modulating proliferation, migration and/or survival of cells. More particularly, the present invention discloses molecules that have any one or more activities selected from: inhibiting binding of vitronectin to at least one vitronectin-binding partner selected from an IGF and IGFBP, inhibiting formation of a complex comprising vitronectin and at least one vitronectin-binding partner selected from an IGF and IGFBP, or inhibiting proliferation or survival of a hyperproliferative cell (e.g., a neoplastic cell or non-neoplastic cell), or inhibiting migration or invasion of a hyperproliferative cell (e.g., a neoplastic cell or a non-neoplastic cell). Additionally, the present invention discloses the use of these molecules in methods and compositions for treating or preventing hyperproliferative cell disorders including neoplastic (e.g., cancers such as epithelial cancers) and non-neoplastic disorders.

主权项

1. An isolated or purified proteinaceous molecule, which consists or consists essentially of an amino acid sequence represented by any one of formulae VII, VIII and I-VI:
X1X2SSEEX3X4X5GX6X7NX8X9X10X11X12X13X14WL  (VII) wherein: X1 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof, and aromatic amino acid residues such as W, or modified forms thereof; X2 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof, and aromatic amino acid residues such as F, or modified forms thereof; X3 is selected from small amino acid residues such as S or T, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as L or V, or modified forms thereof; X4 is selected from small amino acid residues such as G or S, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof; X5 is selected from small amino acid residues such as P, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof; X6 is selected from small amino acid residues such as P, A, G or T, or modified forms thereof; X7 is selected from any amino acid residue including for example neutral/polar amino acid residues such as N, or modified forms thereof, or acidic amino acid residues such as D, or modified forms thereof, or hydrophobic amino acid residues including aromatic amino acid residues such as Y, or modified forms thereof; X8 is absent or is selected from neutral/polar amino acid residues such as N, or modified forms thereof, or hydrophobic amino acid residues including aromatic amino acid residues such Y, or modified forms thereof; X9 is selected from acidic amino acid residues such as E or D, or modified forms thereof, or hydrophobic amino acid residues including aromatic amino acid residues such as Y, or modified forms thereof; X10 is selected from any amino acid residues including acidic amino acid residues such as D, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof, or small amino acid residues such as S, or modified forms thereof; X11 is selected from hydrophobic amino acid residues including aromatic amino acid residues such as Y or F, or modified forms thereof; X12 is selected from charged amino acid residues including basic amino acid residues such as K or R, or modified forms thereof, or acidic amino acid residues such as E or D, or modified forms thereof; X13 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as M, or modified forms thereof, or small amino acid residues such as T, or modified forms thereof; and X14 is selected from any amino acid residues including acidic amino acid residues such as D, or modified forms thereof, or small amino acid residues such as S, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof,
RVNLRTX1RVDX2VX3PPYPRS  (VIII) wherein: X1 is selected from basic amino acid residues such as R, or modified forms thereof, and neutral/polar amino acid residues such as Q, or modified forms thereof; X2 is selected from small amino acid residues such as S, A or T, or modified forms thereof; and X3 is selected from any amino acid residue including for example acidic amino acid residues such as D, or modified forms thereof, or small amino acid residues such as T, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof, or from hydrophobic amino acid residues including aliphatic amino acid residues such as I, or modified forms thereof,
CQCDELCX1YYQSCCX2DX3X4X5  (I) wherein: X1 is selected from small amino acid residues such as S or T, or modified forms thereof; X2 is selected from small amino acid residues such as T or A, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as V, or modified forms thereof; X3 is selected from hydrophobic amino acid residues including aromatic amino acid residues such as Y or F, or modified forms thereof; X4 is selected from small amino acid residues such as T or A, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as M or V, or modified forms thereof; and X5 is selected from small amino acid residues such as A, or modified forms thereof, or acidic amino acid residues such as E, or modified forms thereof,
TX1X2X3GX4X5X6  (II) wherein: X1 is selected from any amino acid residue including for example acidic amino acid residues such as D, or modified forms thereof, or small amino acid residues such as S or T, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof; X2 is selected from charged amino acid residues including basic amino acid residues such as H, or modified forms thereof, or acidic amino acid residues such as D or E, or modified forms thereof; X3 is selected from any amino acid residue including for example small amino acid residues such as P, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof, or neutral/polar amino acid residues such as Q, or modified forms thereof, or acidic amino acid residues such as E, or modified forms thereof; X4 is selected from any amino acid residue including for example basic amino acid residues such as R, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as V, or modified forms thereof, or small amino acid residues such as T, or modified forms thereof; X5 is selected from small amino acid residues such as P or S, or modified forms thereof; and X6 is selected from any amino acid residue including for example neutral/polar amino acid residues such as Q, or modified forms thereof, or acidic amino acid residues such as E, or modified forms thereof, or small amino acid residues such as A, or modified forms thereof,
VDAAX1ALPAHX2X3X4GRERVY  (III) wherein: X1 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof, and aromatic amino acid residues such as F, or modified forms thereof; X2 is selected from any amino acid residue including for example small amino acid residues such as S, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof, or basic amino acid residues such as R, or modified forms thereof; X3 is selected from hydrophobic amino acid residues including aromatic amino acid residues such as Y or F, or modified forms thereof; and X4 is selected from small amino acid residues such as S, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof,
KGX1X2YWEYX3FQX4QPSX5EX6C  (IV) wherein: X1 is selected from charged amino acid residues including basic amino acid residues such as K or modified forms thereof, and acidic amino acid residues such as D, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof; X2 is selected from neutral/polar amino acid residues such as Q, or modified forms thereof, or basic amino acid residues such as H or K, or modified forms thereof; X3 is selected from any amino acid residue including for example neutral/polar amino acid residues such as Q, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as V, or modified forms thereof, or acidic amino acid residues such as E, or modified forms thereof; X4 is selected from basic amino acid residues such as H, or modified forms thereof, or neutral/polar amino acid residues such as Q, or modified forms thereof; X5 is selected from neutral/polar amino acid residues such as Q, or modified forms thereof, or basic amino acid residues such as R, or modified forms thereof; and X6 is selected from acidic amino acid residues such as E or D, or modified forms thereof,
FX1HFAX2X3X4RDSWX5X6IFX7LLFWX8X9X10X11  (V) wherein: X1 is selected from charged amino acid residues including acidic amino acid residues such as E, or modified forms thereof, and basic amino acid residues such as K or modified forms thereof, or small amino acid residues such as A, or modified forms thereof; X2 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as M or L, or modified forms thereof; X3 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as M or L, or modified forms thereof; X4 is selected from neutral/polar amino acid residues such as Q, or modified forms thereof, or basic amino acid residues such H, or modified forms thereof; X5 is selected from acidic amino acid residues such as E, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as V, or modified forms thereof; X6 is selected from acidic amino acid residues such as D, or modified forms thereof, or neutral/polar amino acid residues such as N, or modified forms thereof; X7 is selected from charged amino acid residues including basic amino acid residues such as R or K or modified forms thereof, or acidic amino acid residues such as E, or modified forms thereof; X8 is selected from small amino acid residues such as G or S, or modified forms thereof; X9 is selected from basic amino acid residues such R or H, or modified forms thereof, or small amino acid residues such as G, or modified forms thereof; X10 is selected from small amino acid residues such as T, S or P, or modified forms thereof, and X11 is selected from small amino acid residues such as S, or modified forms thereof, or hydrophobic amino acid residues including aromatic amino acid residues such as F or Y, or modified forms thereof
X1X2X3X4X5GX6X7X8PX9X10ISX11X12WX13GX14PX15  (VI) wherein: X1 is selected from small amino acid residues such as G or S, or modified forms thereof; X2 is selected from basic amino acid residues such as R or H, or modified forms thereof, and small amino acid residues such as G, or modified forms thereof; X3 is selected from small amino acid residues such as T, S or P, or modified forms thereof; X4 is selected from small amino acid residues such as S, or modified forms thereof, or hydrophobic amino acid residues including aromatic amino acid residues such as F or Y, or modified forms thereof; X5 is selected from small amino acid residues such as A or G, or modified forms thereof, or acidic amino acid residues such as D, or modified forms thereof; X6 is selected from small amino acid residues such as T or A, or modified forms thereof; X7 is selected from any amino acid residue including for example basic amino acid residues such as R or K, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as I, or modified forms thereof, or small amino acid residues such as G, or modified forms thereof; X8 is selected from any amino acid residue including for example neutral/polar amino acid residues such as Q, or modified forms thereof, or acidic amino acid residues such E, or modified forms thereof, or small amino acid residues such as G, or modified forms thereof; X9 is selected from neutral/polar amino acid residues such as Q, or modified forms thereof, or basic amino acid residues such R, or modified forms thereof; X10 is selected from hydrophobic amino acid residues including aromatic amino acid residues such as F, or modified forms thereof, and aliphatic amino acid residues such as V or L, or modified forms thereof; X11 is selected from basic amino acid residues such R, or modified forms thereof, or neutral/polar amino acid residues such as Q, or modified forms thereof; X12 is selected from acidic amino acid residues such D, or modified forms, or neutral/polar amino acid residues such as N, or modified forms thereof; X13 is selected from basic amino acid residues such as H, or modified forms thereof, or hydrophobic amino acid residues including aliphatic amino acid residues such as L, or modified forms thereof, and aromatic amino acid residues such as F, or modified forms thereof; X14 is selected from hydrophobic amino acid residues including aliphatic amino acid residues such as V or L, or modified forms thereof; and X15 is selected from small amino acid residues such as G, or modified forms thereof, or acidic amino acid residues such E, or modified forms thereof.