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 K D 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.
Highlights
Overexpression of Grb2-associated binding protein 1 (GAB1) has been observed in several human cancers, such as breast and lung cancers [1,2,3,4]
We have employed intensive computational modeling to understand the structure of the GAB1 pleckstrin homology (PH) domain and screened five million compounds
We found that several inhibitors that induced large conformational changes of the target structure exhibited strong selective binding to GAB1 PH domain
Summary
Overexpression of Grb2-associated binding protein 1 (GAB1) has been observed in several human cancers, such as breast and lung cancers [1,2,3,4]. This protein is a substrate of several growth factors and interleukin receptors, and it is involved in the integration of different signal transductions [1,2,3,4]. GAB1 mediates the activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI-3K) cascades [5,6] It belongs to a family of scaffolding proteins closely related to the insulin receptor substrates (e.g., IRS1) [2]. We attempt to identify novel small molecule inhibitors selectively targeting the PH domain of GAB1 and suggest that these small molecules exhibit high therapeutic potency for cancer treatment
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