TY - JOUR
T1 - PDE6D Inhibitors with a New Design Principle Selectively Block K-Ras Activity
AU - Siddiqui, Farid A.
AU - Alam, Catharina
AU - Rosenqvist, Petja
AU - Ora, Mikko
AU - Sabt, Ahmed
AU - Manoharan, Ganesh Babu
AU - Bindu, Lakshman
AU - Okutachi, Sunday
AU - Catillon, Marie
AU - Taylor, Troy
AU - Abdelhafez, Omaima M.
AU - Lönnberg, Harri
AU - Stephen, Andrew G.
AU - Papageorgiou, Anastassios C.
AU - Virta, Pasi
AU - Abankwa, Daniel
N1 - Funding Information:
This work was supported by a CIMO fellowship to A.S. and F.A.S. P.V. received the support from the Academy of Finland Project (#308931). D.A. received the support from the Academy of Finland Key Project (#304638) grant, the Sigrid Juselius Foundation, and the Cancer Society of Finland.
Funding Information:
The authors are grateful for the support from the cell imaging core (CIC, Turku Bioscience Centre, Turku, Finland). The infrastructure support from Biocenter Finland is acknowledged. We thank Prof. Philippe I. H. Bastiaens (Max-Planck Institute Dortmund, Germany) for providing the mCitrine-Rheb and mCherry-PDEδ constructs. We thank Lange Yakubu Saleh for the synthesis of compound 20 and Anuer Al-Rammahi for the synthesis of compound 17 . We thank Eyad K. Fansa (Max-Planck Institute Dortmund, Germany) for providing the F-Rheb peptide. We acknowledge the protein production support for avi-KRAS-FMe and KRasFMe from Vanessa Wall, Matt Drew, and Jennifer Mehalko and Dominic Esposito for providing the pDest-His6-MBP-PDE6D plasmid (NCI-RAS Initiative, Frederick National Laboratory for Cancer Research, USA). This project was funded in whole or in part with federal funds from National Cancer Institute, NIH Contract HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, and the mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.
Publisher Copyright:
© 2019 American Chemical Society.
PY - 2020/1/14
Y1 - 2020/1/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077450026&partnerID=8YFLogxK
U2 - 10.1021/acsomega.9b03639
DO - 10.1021/acsomega.9b03639
M3 - Article
AN - SCOPUS:85077450026
SN - 2470-1343
VL - 5
SP - 832
EP - 842
JO - ACS Omega
JF - ACS Omega
IS - 1
ER -