Phosphoinositide signaling is a major cellular mechanism controlling cancer cell viability, proliferation, and survival. Yet, inhibition of lipid kinases that produce oncogenic phosphoinositides has afforded only a limited number of efficacious drugs attributed in large part to on-target toxicity resulting from the pleiotropic effects of these signaling lipids. Targeting the specific phosphoinositide effector pathways via competitive inhibitors of phosphoinositide-recognizing pleckstrin homology (PH) domains represents a relatively unexplored means to achieve greater specificity. Herein, we present the discovery from in silico screening, structure–activity relationship (SAR) optimization, and cellular characterization of novel phosphoinositide-competitive inhibitors of the pleckstrin homology domain-containing A (PLEKHA) family. These compounds induce cytotoxic effects in BRAF and NRAS mutant melanoma cells, consistent with on-target inhibition, and the most potent compound is activated by endogenous esterase activity, suggesting that prodrug esters represent a viable strategy for targeting the phosphoinositide-binding pockets of the PLEKHA family of PH domains.

Cornell researchers have uncovered the surprising role played by a “three-tailed” fat molecule in cellular survival during heart attack and stroke: protecting the cells against damage when oxygen runs...

Nature Methods - uMAIA is an analytical framework designed to enable the construction of metabolic atlases at high resolution using mass spectrometry imaging data.

Job #AJO30338, WDR-00054776 Assistant Professor - Chemistry and Chemical Biology, Cornell University (Ithaca, NY), Chemistry and Chemical Biology, Cornell University, Ithaca, New York, US

Directional, non-vesicular lipid transport is responsible for fast, species-selective lipid sorting into organelle membranes.