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Drug discovery

Let K-Ras activate its own inhibitor

Nature Structural & Molecular Biology volume 25, pages 435–437 (2018)Cite this article

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Traditional approaches to covalent drug design postulate that noncovalent binding affinity (Ki) should be in the nanomolar range for the lead compound to be attractive. A study by Hansen et al. suggests that covalent K-Ras inhibitors can have weak noncovalent binding affinity yet have fast chemical reactivity (kinact), because K-Ras enhances the covalent reactivity of bound inhibitor, similarly to how enzymes activate their substrates.

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Fig. 1: Chemical structures of covalent inhibitor of K-Ras and its activation mechanism.

Marina Corral Spence/Springer Nature

Fig. 2: Activation of electrophiles.

Marina Corral Spence/Springer Nature

Fig. 3: Emerging concepts in covalent inhibitor design and discovery of proteins on a proteome-wide scale that can activate bound electrophiles similar to K-Ras.

Marina Corral Spence/Springer Nature

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  1. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, USA

    Alexander V. Statsyuk

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  1. Alexander V. Statsyuk
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Correspondence to Alexander V. Statsyuk.

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Statsyuk, A.V. Let K-Ras activate its own inhibitor. Nat Struct Mol Biol 25, 435–437 (2018). https://doi.org/10.1038/s41594-018-0066-0

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