Development of Selective Phosphatidylinositol 5‑Phosphate 4‑Kinase γ Inhibitors with a Non-ATP-competitive, Allosteric Binding Mode

Phosphatidylinositol 5-phosphate
4-kinases (PI5P4Ks) are emerging
as attractive therapeutic targets in diseases, such as cancer, immunological
disorders, and neurodegeneration, owing to their central role in regulating
cell signaling pathways that are either dysfunctional or can be modulated
to promote cell survival. Different modes of binding may enhance inhibitor
selectivity and reduce off-target effects in cells. Here, we describe
efforts to improve the physicochemical properties of the selective
PI5P4Kγ inhibitor, NIH-12848 (1). These improvements
enabled the demonstration that this chemotype engages PI5P4Kγ
in intact cells and that compounds from this series do not inhibit
PI5P4Kα or PI5P4Kβ. Furthermore, the first X-ray structure
of PI5P4Kγ bound to an inhibitor has been determined with this
chemotype, confirming an allosteric binding mode. An exemplar from
this chemical series adopted two distinct modes of inhibition, including
through binding to a putative lipid interaction site which is 18 Å
from the ATP pocket.