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

Yelland, T. et al. (2022) Stabilization of the RAS:PDE6D complex is a novel strategy to inhibit RAS signaling. Journal of Medicinal Chemistry, 65(3), pp. 1898-1914. (doi: 10.1021/acs.jmedchem.1c01265) (PMID:35104933) (PMCID:PMC8842248)

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.

• Item Type: Articles
• Additional Information: This work was supported by Cancer Research UK core funding number A17196.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Parry, Mr Charles and Pugliese, Dr Angelo and Kowalczyk, Dominika and Bower, Professor Justin and Jamieson, Professor Andrew and Goodwin, Mrs Gillian and Elmaghloob, Yasmin Adel Elsayed and Wojnowska, Marta and Garcia Gonzalez, Dr Esther and Archibald, Dr Lewis and Ismail, Dr Shehab
• Authors: 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., and Ismail, S.
• College/School: College of Medical Veterinary and Life Sciences; College of Medical Veterinary and Life Sciences > School of Cancer Sciences; College of Medical Veterinary and Life Sciences > School of Infection & Immunity; College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Journal of Medicinal Chemistry
• Publisher: American Chemical Society
• ISSN: 0022-2623
• ISSN (Online): 1520-4804
• Published Online: 02 February 2022
• Copyright Holders: Copyright © 2022 The Authors
• First Published: First published in Journal of Medicinal Chemistry 65(3):1898-1914
• Publisher Policy: Reproduced under a Creative Commons License