Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling.

Journal of medicinal chemistry 2022 Feb 10

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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.

Citation

Tamas Yelland, Esther Garcia, Charles Parry, Dominika Kowalczyk, Marta Wojnowska, Andrea Gohlke, Matja Zalar, Kenneth Cameron, Gillian Goodwin, Qing Yu, Peng-Cheng Zhu, Yasmin ElMaghloob, Angelo Pugliese, Lewis Archibald, Andrew Jamieson, Yong Xiang Chen, Duncan McArthur, Justin Bower, Shehab Ismail. Stabilization of the RAS:PDE6D Complex Is a Novel Strategy to Inhibit RAS Signaling. Journal of medicinal chemistry. 2022 Feb 10;65(3):1898-1914