Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells

Lu Chen, Lei Du-Cuny, Sylvestor Moses, Sabrina Dumas, Zuohe Song, Abdol Hossein Rezaeian, Hui Kuan Lin, Emmanuelle Meuillet, Shuxing Zhang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.

Original languageEnglish (US)
JournalPLoS Computational Biology
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2015

Fingerprint

pleckstrin
sequence homology
Breast Cancer
homology
breast neoplasms
Inhibitor
binding proteins
Homology
inhibitor
cancer
Carrier Proteins
Cells
Breast Neoplasms
Protein
protein
Cell
neoplasms
ligand
Ligands
Hits

ASJC Scopus subject areas

  • Computational Theory and Mathematics
  • Modeling and Simulation
  • Ecology, Evolution, Behavior and Systematics
  • Genetics
  • Molecular Biology
  • Ecology
  • Cellular and Molecular Neuroscience

Cite this

Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells. / Chen, Lu; Du-Cuny, Lei; Moses, Sylvestor; Dumas, Sabrina; Song, Zuohe; Rezaeian, Abdol Hossein; Lin, Hui Kuan; Meuillet, Emmanuelle; Zhang, Shuxing.

In: PLoS Computational Biology, Vol. 11, No. 1, 01.01.2015.

Research output: Contribution to journalArticle

Chen, Lu ; Du-Cuny, Lei ; Moses, Sylvestor ; Dumas, Sabrina ; Song, Zuohe ; Rezaeian, Abdol Hossein ; Lin, Hui Kuan ; Meuillet, Emmanuelle ; Zhang, Shuxing. / Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells. In: PLoS Computational Biology. 2015 ; Vol. 11, No. 1.
@article{498ebed3cbf84dc590c11845b1a2a7f5,
title = "Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells",
abstract = "The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.",
author = "Lu Chen and Lei Du-Cuny and Sylvestor Moses and Sabrina Dumas and Zuohe Song and Rezaeian, {Abdol Hossein} and Lin, {Hui Kuan} and Emmanuelle Meuillet and Shuxing Zhang",
year = "2015",
month = "1",
day = "1",
doi = "10.1371/journal.pcbi.1004021",
language = "English (US)",
volume = "11",
journal = "PLoS Computational Biology",
issn = "1553-734X",
publisher = "Public Library of Science",
number = "1",

}

TY - JOUR

T1 - Novel Inhibitors Induce Large Conformational Changes of GAB1 Pleckstrin Homology Domain and Kill Breast Cancer Cells

AU - Chen, Lu

AU - Du-Cuny, Lei

AU - Moses, Sylvestor

AU - Dumas, Sabrina

AU - Song, Zuohe

AU - Rezaeian, Abdol Hossein

AU - Lin, Hui Kuan

AU - Meuillet, Emmanuelle

AU - Zhang, Shuxing

PY - 2015/1/1

Y1 - 2015/1/1

N2 - The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.

AB - The Grb2-associated binding protein 1 (GAB1) integrates signals from different signaling pathways and is over-expressed in many cancers, therefore representing a new therapeutic target. In the present study, we aim to target the pleckstrin homology (PH) domain of GAB1 for cancer treatment. Using homology models we derived, high-throughput virtual screening of five million compounds resulted in five hits which exhibited strong binding affinities to GAB1 PH domain. Our prediction of ligand binding affinities is also in agreement with the experimental KD values. Furthermore, molecular dynamics studies showed that GAB1 PH domain underwent large conformational changes upon ligand binding. Moreover, these hits inhibited the phosphorylation of GAB1 and demonstrated potent, tumor-specific cytotoxicity against MDA-MB-231 and T47D breast cancer cell lines. This effort represents the discovery of first-in-class GAB1 PH domain inhibitors with potential for targeted breast cancer therapy and provides novel insights into structure-based approaches to targeting this protein.

UR - http://www.scopus.com/inward/record.url?scp=84922213176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84922213176&partnerID=8YFLogxK

U2 - 10.1371/journal.pcbi.1004021

DO - 10.1371/journal.pcbi.1004021

M3 - Article

VL - 11

JO - PLoS Computational Biology

JF - PLoS Computational Biology

SN - 1553-734X

IS - 1

ER -