Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling
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RAS is a major anticancer drug target which requires membrane localization to activate downstream signal transduction. The direct inhibition of RAS has proven to be challenging. Here, we present a novel strategy for targeting RAS by stabilizing its interaction with the prenyl-binding protein PDE6D and disrupting its localization. Using rationally designed RAS point mutations, we were able to stabilize the RAS:PDE6D complex by increasing the affinity of RAS for PDE6D, which resulted in the redirection of RAS to the cytoplasm and the primary cilium and inhibition of oncogenic RAS/ERK signaling. We developed an SPR fragment screening and identified fragments that bind at the KRAS:PDE6D interface, as shown through cocrystal structures. Finally, we show that the stoichiometric ratios of KRAS:PDE6D vary in different cell lines, suggesting that the impact of this strategy might be cell-type-dependent. This study forms the foundation from which a potential anticancer small-molecule RAS:PDE6D complex stabilizer could be developed.
Yelland , T , Garcia , E , Parry , C , Kowalczyk , D , Wojnowska , M , Gohlke , A , Zalar , M , Cameron , K , Goodwin , G , Yu , Q , Zhu , P-C , ElMaghloob , Y , Pugliese , A , Archibald , L , Jamieson , A , Chen , Y X , McArthur , D , Bower , J & Ismail , S 2022 , ' Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling ' , Journal of Medicinal Chemistry , vol. 65 , no. 3 , pp. 1898-1914 . https://doi.org/10.1021/acs.jmedchem.1c01265
Journal of Medicinal Chemistry
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DescriptionThis work was supported by Cancer Research UK core funding number A17196.
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