The Grb2-associated binder-1 (GAB1) over-expressed in many cancers represents a novel therapeutic target that integrates signals from different systems such as MET and PI3K/Akt pathways. It mediates processes involved in tumor progression and metastasis. In this study we have identified novel inhibitors targeting the pleckstrin homology (PH) domain of GAB1 for cancer treatment. To this end, a homology model of GAB1 PH domain was constructed, followed by structural refinement using molecular dynamics. The resulting structure was applied to high-throughput virtual screening of 5 million compounds and 19 hits were selected for experimental evaluation. We found that 6 compounds bound to the PH domain of GAB1 as measured by surface plasmon resonance spectroscopy, with a KD. Out of these 6 hits, all of them inhibited the HGF-I induced phosphorylation of GAB1 Tyr627 in T47D and inhibited T47D and MDA-MB-231 breast cancer cell lines proliferation. Three of them exhibited selective binding to GAB1 PH domain as compared to the PH domain of IRS-1 and AKT. This demonstrates for the first time the identification of novel GAB1 PH domain inhibitors which may be used for targeted breast cancer therapy.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2166. doi:1538-7445.AM2012-2166