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 to oncogenic pathways. Herein we present the discovery from in silico screening and SAR optimization of ligands to several members of the PLEKHA family of PH domain-containing proteins. These compounds, from two distinct chemotypes, displace the phosphoinositide head group with high nanomolar to low micromolar affinity and induce cytotoxic effects in BRAF- and NRAS-mutant melanoma, as well as osteosarcoma cell lines with micromolar EC50 values in a PARP- and CASP3-dependent manner. Taken together, this study builds on previous biological studies implicating PLEKHA family proteins as phosphoinositide signaling effectors that are promising anticancer targets and identifies two drug-like chemotypes targeting these proteins that exhibit cytotoxicity in a variety of cancer cell lines.