Discovery, Optimization, and Anticancer Activity of Lipid-Competitive Pleckstrin Homology Domain-Containing Family A Inhibitors

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.