Fendiline Inhibits K-Ras Plasma Membrane Localization and Blocks K-Ras Signal Transmission

Social Interactomes for Enabling Research Communities

“…In 2014, areas with promising achievements changed considerably as compared with previous years, with major interest in drug design for direct or indirect RAS targeting, preclinicalclinical translation with novel agents and combinations of targeted therapies in RAS/RAF-driven models, the role of oncogenic KRAS in metabolic reprogramming, and its interaction with the tumor microenvironment. Top publications in the field repeatedly mentioned by respondents reported the development of compounds that bind to well-defined surface pockets on oncogenic KRAS in a mutant-specific manner (2,3) or that inhibit its interaction with plasma membrane/ scaffold proteins (4,5). In line with these findings, in 2013, the most pressing question for RAS scientists concerned the druggability of KRAS, whereas in 2014, investigators were mainly interested in preclinical-clinical translation of KRASinteracting agents.…”

Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling

“…Cells transformed by either K-Ras or H-Ras also show altered ganglioside levels (Suzuki et al, 1989) and oncogenic K-Ras activity can be regulated by the levels of PM PS van der Hoeven et al, 2013). We have previously analyzed changes in the expression of genes associated with lipid regulation comparing CAV1 +/+ and CAV1 / mouse embryonic fibroblasts (MEFs).…”

“…In consequence, H-and K-Ras assemble into spatially nonoverlapping nanoclusters with further lateral segregation into nonoverlapping GDP and GTP nanoclusters (Prior et al, 2003a;Plowman et al, 2005Plowman et al, , 2008Roy et al, 2005;Zhou et al, 2012). H-Ras associates with cholesterol-dependent nanoclusters on the inner leaflet of the PM when in an inactive GDP-bound state and, upon GTP loading, switches to cholesterol-insensitive nanodomains; K-Ras occupies cholesterol-insensitive nanoclusters in both GTP-and GDP-bound states that have been closely linked with phosphatidylserine (PS; Cho et al, 2012;van der Hoeven et al, 2013). Ras.GTP nanoclusters are the sole sites of effector recruitment and activation on the PM (Hibino et al, 2003;Murakoshi et al, 2004;Tian et al, 2007;Plowman et al, 2008), such that Ras signal transmission is abrogated if MEFs (n = 6).…”

“…Caveolae regulate the nanoscale organization of the plasma membrane to remotely control Ras signaling nanoclustering is inhibited, or nanocluster structure is perturbed Tian et al, 2007;Cho et al, 2012;Zhou et al, 2012;van der Hoeven et al, 2013).…”

Andrographolide derivatives inhibit guanine nucleotide exchange and abrogate oncogenic Ras function

“…Attempts to abrogate the plasma membrane binding of Ras, which is required for biological activity, by inhibiting farnesyl transferase (6,7) have failed because N-Ras and K-Ras are also good substrates for geranylgeranyl transferase 1 in cells treated with farnesyl transferase inhibitors (8,9). Other efforts along this line include the development of farnesyl analogs, currently in clinical trials (10), and other compounds that dislodge Ras from the plasma membrane (11,12). Although the potential therapeutic value and mechanism of action of these compounds are still under investigation, it is clear that they do not directly bind to Ras.…”