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.

The class I phosphoinositide 3-kinase pathway (PI3K) is a master regulator of cellular growth, and plays essential roles in controlling immune cell fu…

Protein kinases are master regulators of myriad processes in eukaryotic cells playing critical roles in growth, metabolism, cellular differentiation, and motility. A subclass of protein kinases is reg...

Join us at Chemsymposia 2026 to discover groundbreaking research in physics applications. Connect with experts, engage in insightful discussions, and explore our venue, registration details, and speak...

PI3Kα is a potent oncogene that converts PIP2 to PIP3 at the plasma membrane upon activation by receptor tyrosine kinases and Ras GTPases. In the absence of any structures of activated PI3Kα, the mole...

In this paper, Pemberton et al. describe the generation and characterization of an engineered active fragment of the PIKfyve enzyme and its use to generate

A dynamic substrate adapter (DET1) recruits COP1 to Cullin ubiquitin ligase complexes assisted by a noncatalytic E2 enzyme.

Holmes and colleagues show that AKT activation is blocked by commonly used PIP3 biosensors, but that this can be overcome by expressing biosensors at singl

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders ...

The structure of the EFR3A-PI4KA complex reveals insight into PI4KA membrane localization and its role in human disease.