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