PDE6D Inhibitors
with a New Design Principle Selectively
Block K‑Ras Activity
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
10.1021/acsomega.9b03639.s001
https://acs.figshare.com/articles/journal_contribution/PDE6D_Inhibitors_with_a_New_Design_Principle_Selectively_Block_K_Ras_Activity/11438862
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.
2019-12-23 09:29:22
PDE 6D
trafficking chaperone PDE 6D
cell penetration
K-Ra
PDE 6D Inhibitors
breast cancer cells
UNC
ejection
PDE 6D inhibitors
H-Ras membrane organization
block stemness traits
4B
model compounds
prenyl-binding pocket inhibitors