Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)1898-1914
Number of pages17
JournalJournal of Medicinal Chemistry
Volume65
Issue number3
Early online date1 Feb 2022
DOIs
Publication statusPublished - 10 Feb 2022

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