Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

Philip C. Simister; James Luccarelli; Sam Thompson; Daniel H. Appella; Stephan M. Feller; Andrew D. Hamilton

doi:10.1016/j.bmc.2012.10.023

Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

Philip C. Simister, James Luccarelli, Sam Thompson, Daniel H. Appella, Stephan M. Feller, Andrew D. Hamilton

Chemistry

Research output: Contribution to journal › Article › peer-review

Abstract

The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 ₁₀ helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC₅₀ 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.

Original language	English (US)
Pages (from-to)	4027-4033
Number of pages	7
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2012.10.023
State	Published - Jul 15 2013

Keywords

Gab2
Grb2
Inhibitors
Protein-protein interaction
SH3 Domain
Virtual screening

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

Access to Document

10.1016/j.bmc.2012.10.023

Cite this

@article{1dc718e67f7d4f58b9bc2d7bcd7f1a41,

title = "Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen",

abstract = "The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 10 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.",

keywords = "Gab2, Grb2, Inhibitors, Protein-protein interaction, SH3 Domain, Virtual screening",

author = "Simister, {Philip C.} and James Luccarelli and Sam Thompson and Appella, {Daniel H.} and Feller, {Stephan M.} and Hamilton, {Andrew D.}",

note = "Funding Information: We thank the Oxford Cancer Research Centre Development Fund and the Rosetrees Trust (PCS and SF), Breast Cancer Campaign and Cancer Research UK (SF) Cancer Research UK (SF), the University of Oxford (JL and ST), the Marshall Aid Commemoration Commission and Oriel College, Oxford (JL) for funding. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. ( http://biowulf.nih.gov ). ",

year = "2013",

month = jul,

day = "15",

doi = "10.1016/j.bmc.2012.10.023",

language = "English (US)",

volume = "21",

pages = "4027--4033",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

publisher = "Elsevier Limited",

number = "14",

}

TY - JOUR

T1 - Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

AU - Simister, Philip C.

AU - Luccarelli, James

AU - Thompson, Sam

AU - Appella, Daniel H.

AU - Feller, Stephan M.

AU - Hamilton, Andrew D.

N1 - Funding Information: We thank the Oxford Cancer Research Centre Development Fund and the Rosetrees Trust (PCS and SF), Breast Cancer Campaign and Cancer Research UK (SF) Cancer Research UK (SF), the University of Oxford (JL and ST), the Marshall Aid Commemoration Commission and Oriel College, Oxford (JL) for funding. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Md. ( http://biowulf.nih.gov ).

PY - 2013/7/15

Y1 - 2013/7/15

N2 - The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 10 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.

AB - The adaptor protein Grb2 links cell-surface receptors, such as Her2, to the multisite docking proteins Gab1 and 2, leading to cell growth and proliferation in breast and other cancers. Gab2 interacts with the C-terminal SH3 domain (SH3C) of Grb2 through atypical RxxK motifs within polyproline II or 3 10 helices. A virtual screen was conducted for putative binders of the Grb2 SH3C domain. Of the top hits, 34 were validated experimentally by surface plasmon resonance spectroscopy and isothermal titration calorimetry. A subset of these molecules was found to inhibit the Grb2-Gab2 interaction in a competition assay, with moderate to low affinities (5: IC50 320 μM). The most promising binders were based on a dihydro-s-triazine scaffold, and are the first small molecules reported to target the Grb2 SH3C protein-interaction surface.

KW - Gab2

KW - Grb2

KW - Inhibitors

KW - Protein-protein interaction

KW - SH3 Domain

KW - Virtual screening

UR - http://www.scopus.com/inward/record.url?scp=84879012629&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879012629&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.10.023

DO - 10.1016/j.bmc.2012.10.023

M3 - Article

C2 - 23182216

AN - SCOPUS:84879012629

SN - 0968-0896

VL - 21

SP - 4027

EP - 4033

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 14

ER -

Novel inhibitors of a Grb2 SH3C domain interaction identified by a virtual screen

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this