Files in this item
Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling
Item metadata
dc.contributor.author | Yelland, Tamas | |
dc.contributor.author | Garcia, Esther | |
dc.contributor.author | Parry, Charles | |
dc.contributor.author | Kowalczyk, Dominika | |
dc.contributor.author | Wojnowska, Marta | |
dc.contributor.author | Gohlke, Andrea | |
dc.contributor.author | Zalar, Matja | |
dc.contributor.author | Cameron, Kenneth | |
dc.contributor.author | Goodwin, Gillian | |
dc.contributor.author | Yu, Qing | |
dc.contributor.author | Zhu, Peng-Cheng | |
dc.contributor.author | ElMaghloob, Yasmin | |
dc.contributor.author | Pugliese, Angelo | |
dc.contributor.author | Archibald, Lewis | |
dc.contributor.author | Jamieson, Andrew | |
dc.contributor.author | Chen, Yong Xiang | |
dc.contributor.author | McArthur, Duncan | |
dc.contributor.author | Bower, Justin | |
dc.contributor.author | Ismail, Shehab | |
dc.date.accessioned | 2022-02-11T16:30:19Z | |
dc.date.available | 2022-02-11T16:30:19Z | |
dc.date.issued | 2022-02-10 | |
dc.identifier | 277707692 | |
dc.identifier | a84c7b97-3a9d-4a65-880f-05f76cd5e63b | |
dc.identifier | 85124439248 | |
dc.identifier | 000797933300017 | |
dc.identifier.citation | 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 | en |
dc.identifier.issn | 0022-2623 | |
dc.identifier.other | RIS: urn:01AEDD74D620D6B9C1969D20731E9815 | |
dc.identifier.uri | https://hdl.handle.net/10023/24858 | |
dc.description | This work was supported by Cancer Research UK core funding number A17196. | en |
dc.description.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. | |
dc.format.extent | 17 | |
dc.format.extent | 10872720 | |
dc.language.iso | eng | |
dc.relation.ispartof | Journal of Medicinal Chemistry | en |
dc.subject | QD Chemistry | en |
dc.subject | DAS | en |
dc.subject | AC | en |
dc.subject.lcc | QD | en |
dc.title | Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling | en |
dc.type | Journal article | en |
dc.contributor.institution | University of St Andrews. School of Chemistry | en |
dc.identifier.doi | 10.1021/acs.jmedchem.1c01265 | |
dc.description.status | Peer reviewed | en |
This item appears in the following Collection(s)
Items in the St Andrews Research Repository are protected by copyright, with all rights reserved, unless otherwise indicated.