Chapter 20. Cell Adhesion Integrins as Pharmaceutical Targets

doi:10.1016/S0065-7743(08)60459-5

Annual Reports in Medicinal Chemistry

Volume 31, 1996, Pages 191-200

https://doi.org/10.1016/S0065-7743(08)60459-5 Get rights and content

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Integrin research is rapidly evolving. Anti-platelet agents are in the clinic and discovery efforts are ranging across a spectrum of opportunities for the treatment of disease, both metabolic and infectious. The complex, dynamically regulated phenotypic expression of plasma membrane linked glycoprotein and carbohydrate molecules and their ability to uniquely recognize soluble and insoluble ligands helps define the biological basis of current concepts of development, life, and death. As understanding of the pivotal role of cell adhesion and communication in normal life processes improves, further discernment of the consequences of atypical adhesion and communication becomes possible. The promise of more lucid molecular pathology is modification of disease states through drug treatment. This chapter discusses the integrin class of cell adhesion molecules. The focus remains toward the pathologies for which disease modifying agents could be developed based on the understanding of the specific molecular interactions. The integrin superfamily is made up of structurally and functionally related glycoproteins distributed over three families— namely, the very late antigens (VLA) family (β₁), the Leucam family (β₂), and the cytoadhesin family (β₃). Integrins are α,β heterodimeric, transmembrane receptor molecules found in combinations on every mammalian cell type except red blood cells. There are 15 α subunits and 8 β subunits that are noncovalently linked and expressed on the surfaces of cells in combination. The integrin name has been derived from their role in “integrating” the extracellular matrix (ECM) with the cytoskeleton.

References (126)

R.O. Hynes
Cell
(1987)
F. Altruda et al.
Gene
(1990)
P.F. Bray et al.
J. Biol. Chem.
(1990)
R.O. Hynes
Cell
(1992)
C. Berlin et al.
Cell
(1993)
D.T. Crowe et al.
J. Biol. Chem.
(1994)
M. Busk et al.
J. Biol. Chem.
(1992)
D. Sheppard et al.
J. Biol. Chem.
(1990)
M.V. Agrez et al.
Eur. J. Cancer
(1994)
S.L. Nishimura et al.
J. Biol. Chem.
(1994)

R. Briesewitz et al.

Mol. Biol. Cell

(1995)

(1995)

J.M. Breuss et al.

J. Histochem. Cytochem.

(1993)

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Constraining the amide bond in N-Sulfonylated dipeptide VLA-4 antagonists
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The integrin VLA-4 is implicated in several inflammatory disease states. In search of non-peptidic antagonists of VLA-4, rotational constraints were imposed on the amide bond of prototypical N-sulfonylated dipeptide VLA-4 antagonists. By judicious structural modification of the side chains, trisubstituted imidazoles with moderate binding potencies were obtained, for example, 19, VLA-4 IC₅₀ = 237 nM.
Highly constrained bicyclic VLA-4 antagonists
2007, Bioorganic and Medicinal Chemistry Letters
VLA-4 is implicated in several inflammatory and autoimmune disease states. A series of cyclic β-amino acids (β-aa) was studied as VLA-4 antagonists. Binding affinity was highly dependent on the dihedral angle (ϕ) between the amino and the carboxyl termini of the β-aa. Compound 5m where the β-aa is embedded in a bicycle possesses the most preferred ϕ (120°). It is a potent and bioavailable VLA-4 antagonist (VCAM-Ig α4β1 IC₅₀ = 54 nM, rat po F = 49%).
A Survey of Novel Molecular Targets for Anticancer Drug Discovery
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This chapter provides a general survey of validated and emerging molecular targets for cancer drug discovery and development, with a focus on those explored for the discovery of molecularly targeted cancer therapeutics. The targeting of oncogenic protein tyrosine kinase signal transduction pathways in cancer cells ushered in the molecularly targeted approach to therapeutics. The signaling cascade is initiated by the growth factors binding to their cognate receptor tyrosine kinases (RTKs) at the extracellular domain. Protein and lipid kinases modulate the cellular functions of numerous other proteins and play critical roles in signal transduction pathways of cell growth and proliferation. The chapter explains the major receptor and cytosolic tyrosine kinases identified as novel cancer targets. It is found that, in addition to the HER or erbB family of oncogenic RTKs, several other RTKs constitute potential novel molecular targets for cancer drug discovery such as the platelet-derived growth factor receptor. The transcription factor hypoxia-inducible factor has also been shown to be important in cancer progression and angiogenesis. Its overexpression has been correlated with treatment failure and mortality in brain, breast, cervical, esophageal, oropharyngeal, and ovarian cancers.
A Survey of Novel Molecular Targets for Anticancer Drug Discovery
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This chapter provides a general survey of validated and emerging molecular targets for cancer drug discovery and development, with a focus on those explored for the discovery of molecularly targeted cancer therapeutics. The targeting of oncogenic protein tyrosine kinase signal transduction pathways in cancer cells ushered in the molecularly targeted approach to therapeutics. The signaling cascade is initiated by the growth factors binding to their cognate receptor tyrosine kinases (RTKs) at the extracellular domain. Protein and lipid kinases modulate the cellular functions of numerous other proteins and play critical roles in signal transduction pathways of cell growth and proliferation. The chapter explains the major receptor and cytosolic tyrosine kinases identified as novel cancer targets. It is found that, in addition to the HER or erbB family of oncogenic RTKs, several other RTKs constitute potential novel molecular targets for cancer drug discovery such as the platelet-derived growth factor receptor. The transcription factor hypoxia-inducible factor has also been shown to be important in cancer progression and angiogenesis. Its overexpression has been correlated with treatment failure and mortality in brain, breast, cervical, esophageal, oropharyngeal, and ovarian cancers.
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A peptidomimetic, 2-amino-6-[(2-amino-5{guanidino}pentanoyl) amino] hexanoic acid, was synthesized using Lys and Arg to produce a compound that mimics the biological activity of a cell adhesive Arg–Gly–Asp (RGD) peptide, GRGDSP. When immobilized on solid substrates, the peptidomimetic promoted cell adhesion similar to substrates with immobilized GRGDSP. Ligand competition studies demonstrated that cell interactions with the peptidomimetic were integrin-mediated. The peptidomimetic was very stable to proteolytic degradation in comparison to proteolytically unstable peptides. Both GRGDSP and peptidomimetic were stabilized when immobilized on solid substrates. This peptidomimetic has the broad therapeutic utility of the RGD peptides with higher stability and potentially enhanced therapeutic efficacy.
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Chapter 20. Cell Adhesion Integrins as Pharmaceutical Targets

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Cell

Gene

J. Biol. Chem.

Cell

Cell

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Eur. J. Cancer

J. Biol. Chem.

Exp. Cell Res.

J. Biol. Chem.

Curr. Opin. Cell Biol.

J. Biol. Chem.

Curr. Opin. Cell Biol.

Science

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

J. Vasc. Surg.

Peptides

Eur. J. Cancer

Cell

Cell Adhes. Commun.

Proc. Natl. Acad. Sci. USA

J. Cell. Biol.

J. Cell Biol

Proc. Natl. Acad. Sci. USA

EMBO J.

EMBO J.

J. Cell. Biol.

Cell. Adhes. Commun.

J. Cell. Sci.

Proc. Natl. Acad. Sci. USA

Eur. J. Biochem.

Cell. Biol.

Mol. Biol. Cell

Nature

Eur. J. Immunol.

Proc. Natl. Acad. Sci. USA

Eur. J. Immunol.

Int. Immunol.

J. Immunol.

Eur. J. Immunol.

Eur. J. Immunol.

J. Immunol.

Eur. J. Immunol.

J. Histochem. Cytochem.