Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2

Nathalie Meurice, Lei Wang, Christopher A. Lipinski, Zhongbo Yang, Christopher Hulme, Joseph C. Loftus

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases.

Original languageEnglish (US)
Pages (from-to)669-677
Number of pages9
JournalJournal of Medicinal Chemistry
Volume53
Issue number2
DOIs
StatePublished - 2010

Fingerprint

Focal Adhesion Kinase 2
Focal Adhesion Protein-Tyrosine Kinases
Glioma
Site-Directed Mutagenesis
Protein-Tyrosine Kinases
Libraries
Cell Movement
Monoclonal Antibodies
Cell Proliferation
Ligands
Proteins
ezrin
radixin
moesin
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2. / Meurice, Nathalie; Wang, Lei; Lipinski, Christopher A.; Yang, Zhongbo; Hulme, Christopher; Loftus, Joseph C.

In: Journal of Medicinal Chemistry, Vol. 53, No. 2, 2010, p. 669-677.

Research output: Contribution to journalArticle

Meurice, Nathalie ; Wang, Lei ; Lipinski, Christopher A. ; Yang, Zhongbo ; Hulme, Christopher ; Loftus, Joseph C. / Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 2. pp. 669-677.
@article{f31ce974bfbc47029d99bd0c7a4efe90,
title = "Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2",
abstract = "The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases.",
author = "Nathalie Meurice and Lei Wang and Lipinski, {Christopher A.} and Zhongbo Yang and Christopher Hulme and Loftus, {Joseph C.}",
year = "2010",
doi = "10.1021/jm901247a",
language = "English (US)",
volume = "53",
pages = "669--677",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - Structural conservation in band 4.1, ezrin, radixin, moesin (FERM) domains as a guide to identify inhibitors of the proline-rich tyrosine kinase 2

AU - Meurice, Nathalie

AU - Wang, Lei

AU - Lipinski, Christopher A.

AU - Yang, Zhongbo

AU - Hulme, Christopher

AU - Loftus, Joseph C.

PY - 2010

Y1 - 2010

N2 - The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases.

AB - The nonreceptor focal adhesion kinases FAK and Pyk2 play a central role in the regulation of glioma cell proliferation and migration, making them attractive targets to improve clinical outcome. Noncatalytic targeting represents a novel approach to regulate the activity of these tyrosine kinases. A combination of site directed mutagenesis and molecular modeling was used to identify compounds that target the F3 module of the Pyk2 FERM domain. A protein pharmacophore model for the Pyk2 FERM/F3 module, generated utilizing the structural conservation of ligand-bound FERM domains with known 3D structures, was used to search the LeadQuest compound library. Compounds compliant with the model were tested for their ability to inhibit the binding of a monoclonal antibody that maps to a functional site on the F3 module. The highest scoring compound bound directly to the Pyk2 FERM domain, inhibited Pyk2 stimulated glioma migration, and provides the framework for the development of novel therapeutic agents to target the activity of the focal adhesion kinases.

UR - http://www.scopus.com/inward/record.url?scp=77249142358&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77249142358&partnerID=8YFLogxK

U2 - 10.1021/jm901247a

DO - 10.1021/jm901247a

M3 - Article

C2 - 20017492

AN - SCOPUS:77249142358

VL - 53

SP - 669

EP - 677

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 2

ER -