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.
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Lei
authors.initials: L
authors.lastname: Du-Cuny
authors.affiliation: Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Sylvestor
authors.initials: S
authors.lastname: Moses
authors.affiliation: Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Dumas
authors.affiliation: Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Zuohe
authors.initials: Z
authors.lastname: Song
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Abdol Hossein
authors.initials: AH
authors.lastname: Rezaeian
authors.affiliation: Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Hui-Kuan
authors.initials: HK
authors.lastname: Lin
authors.affiliation: Departments of Nutritional Sciences and Molecular and Cellular Biology, the University of Arizona Cancer Center, Tucson, Arizona, United States of America.
authors.forename: Emmanuelle J
authors.initials: EJ
authors.lastname: Meuillet
authors.affiliation: Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Shuxing
authors.initials: S
authors.lastname: Zhang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001798:Blood Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D005260:Female; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011485:Protein Binding; D016415:Sequence Alignment; D013816:Thermodynamics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001798:Blood Proteins; C098587:GAB1 protein, human; D010750:Phosphoproteins; C039077:platelet protein P47