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

A1 Journal article (refereed)

Internal Authors/Editors

Publication Details

List of Authors: Farid A. Siddiqui, Catharina Alam, Petja Rosenqvist, Mikko Ora, Ahmed Sabt, Ganesh babu Manoharan, Lakshman Bindu, Sunday Okutachi, Marie Catillon, Troy Taylor, Omaima M. Abdelhafez, Harri Lönnberg, Andrew G. Stephen, Anastassios C. Papageorgiou, Pasi Virta, Daniel Abankwa
Publisher: ACS
Publication year: 2019
Journal: ACS Omega
Volume number: 5
Issue number: 1
Start page: 832
End page: 842
eISSN: 2470-1343


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

Last updated on 2020-04-06 at 04:24