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 J. Meuillet, Shuxing Zhang

Research output: Contribution to journalArticle

11 Scopus citations

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

ASJC Scopus subject areas

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

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