PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity

Siddiqui, Farid A; Alam, Catharina; Ora, Mikko; Sabt, Ahmed; Manoharan, Ganesh Babu; Bindu, Lakshman; Okutachi, Sunday; Catillon, Marie; Taylor, Troy; Abdelhafez, Omaima M; L�nnberg, Harri; Stephen, Andrew G; Papageorgiou, Anastassios C; Virta, Pasi; Abankwa, Daniel

Abstract

The trafficking chaperone PDE6D (also referred to as PDEδ) has been nominated as a surrogate target for K-Ras4B (hereafter K-Ras). Arl2-assisted unloading of K-Ras from PDE6D in the perinuclear area is significant for correct K-Ras localization and therefore activity. However, the unloading mechanism also leads to the undesired ejection of PDE6D inhibitors. To counteract ejection, others have recently optimized inhibitors for picomolar affinities; however, cell penetration generally seems to remain an issue. To increase resilience against ejection, we engineered a "chemical spring" into prenyl-binding pocket inhibitors of PDE6D. Furthermore, cell penetration was improved by attaching a cell-penetration group, allowing us to arrive at micromolar in cellulo potencies in the first generation. Our model compounds, Deltaflexin-1 and -2, selectively disrupt K-Ras, but not H-Ras membrane organization. This selectivity profile is reflected in the antiproliferative activity on colorectal and breast cancer cells, as well as the ability to block stemness traits of lung and breast cancer cells. While our current model compounds still have a low in vitro potency, we expect that our modular and simple inhibitor redesign could significantly advance the development of pharmacologically more potent compounds against PDE6D and related targets, such as UNC119 in the future.

Citation

Siddiqui, F. A., Alam, C., Ora, M., Sabt, A., Manoharan, G. B., Bindu, L., Okutachi, S., Catillon, M., Taylor, T., Abdelhafez, O. M., Lönnberg, H., Stephen, A. G., Papageorgiou, A. C., Virta, P., & Abankwa, D. (2020). PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity. ACS Omega, 5(1), 832-842. https://doi.org/10.1021/acsomega.9b03639

• Journal Article Type: Article
• Acceptance Date: Dec 9, 2019
• Online Publication Date: Dec 23, 2019
• Publication Date: 2020-01
• Deposit Date: May 11, 2022
• Publicly Available Date: May 11, 2022
• Journal: ACS omega
• Print ISSN: 2470-1343
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 5
• Issue: 1
• Pages: 832-842
• DOI: https://doi.org/10.1021/acsomega.9b03639
• Public URL: http://researchrepository.napier.ac.uk/Output/2869913
• Publisher URL: https://europepmc.org/articles/PMC6964506