AI Article Synopsis
- The protein PDEδ plays a critical role in facilitating K-Ras movement throughout the cytosol by binding to it.
- Researchers have developed small molecules that inhibit the interaction between K-Ras and PDEδ, showing high binding affinity and potential for new cancer treatments targeting K-Ras mutations.
Article Abstract
K-Ras is one of the most frequently mutated signal transducing human oncogenes. Ras signaling activity requires correct cellular localization of the GTPase. The spatial organization of K-Ras is controlled by the prenyl binding protein PDEδ, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling. Here we describe in detail the identification and structure guided development of Ras-PDEδ inhibitors targeting the farnesyl binding pocket of PDEδ with nanomolar affinity. We report kinetic data that characterize the binding of the most potent small molecule ligands to PDEδ and prove their binding to endogenous PDEδ in cell lysates. The PDEδ inhibitors provide promising starting points for the establishment of new drug discovery programs aimed at cancers harboring oncogenic K-Ras.
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| http://dx.doi.org/10.1021/jm500632s | DOI Listing |
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