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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


Farid A Siddiqui

Mikko Ora

Ahmed Sabt

Ganesh Babu Manoharan

Lakshman Bindu

Sunday Okutachi

Marie Catillon

Troy Taylor

Omaima M Abdelhafez

Harri L�nnberg

Andrew G Stephen

Anastassios C Papageorgiou

Pasi Virta

Daniel Abankwa


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.

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
Public URL
Publisher URL


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