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

DOI: 10.1021/acs.jmedchem.1c01265 DOI Help

Authors: Tamas Yelland (CRUK Beatson Institute) , Esther Garcia (CRUK Beatson Institute) , Charles Parry (CRUK Beatson Institute) , Dominika Kowalczyk (CRUK Beatson Institute) , Marta Wojnowska (University of St Andrews) , Andrea Gohlke (CRUK Beatson Institute) , Matja Zalar (CRUK Beatson Institute; University of Manchester) , Kenneth Cameron (CRUK Beatson Institute) , Gillian Goodwin (CRUK Beatson Institute; BioAscent Discovery Ltd) , Qing Yu (Tsinghua University) , Peng-Cheng Zhu (Tsinghua University) , Yasmin Elmaghloob (CRUK Beatson Institute) , Angelo Pugliese (CRUK Beatson Institute; BioAscent Discovery Ltd) , Lewis Archibald (University of Glasgow) , Andrew Jamieson (University of Glasgow) , Yong Xiang Chen (Tsinghua University) , Duncan Mcarthur (CRUK Beatson Institute; BioAscent Discovery Ltd,) , Justin Bower (CRUK Beatson Institute) , Shehab Ismail (CRUK Beatson Institute; KU Leuven)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 12

State: Published (Approved)
Published: February 2022

Open Access Open Access

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.

Journal Keywords: Peptides and proteins; Genetics; Monomers; Conformation; Screening assays

Subject Areas: Biology and Bio-materials, Chemistry, Medicine

Instruments: I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: Swiss Light Source

Added On: 03/02/2022 14:29

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)