Guanine nucleotide exchange factors (GEFs) are a class of multi-domain proteins involved in the activation of small GTPases. Although GEFs are viewed as potential drug targets relevant for human diseases, they are highly dynamic in nature which makes it challenging to modulate their function with low molecular weight (LMW) compounds. We will report on the discovery and mode of action characterization of a series of soluble and permeable small molecular weight compounds that have been discovered as potent and selective inhibitors of the VAV1-GEF dependent activation of the Rho family GTP binding protein RAC1. We could demonstrate that these compounds show iso-form selective VAV1-inhibition in biochemical assays, and significant isoform-selective VAV1-mediated inhibitory effects in cellular assays. From analysis of inhibitor-VAV1 co-crystal structures we could conclude that compound binding induces conformational changes preventing VAV1 binding to RAC1 through an allosteric mechanism, revealing a previously unrecognized functional compound binding site between the C1- and DH-domains of VAV1.

Discovery of selective low molecular weight VAV1 guanine nucleotide exchange factor inhibitors

254th National Meeting (2017)

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