PI5P4K inhibitors: promising opportunities and challenges.

Phosphatidylinositol 5-phosphate 4-kinases (PI5P4K), also known as type II PIPKs or PIPKIIs, convert the lipid second messenger PI5P to PI(4,5)P₂. The PI5P4K family consists of three isozymes in mammals-PI5P4Kα, β, and γ-which notably utilize both GTP and ATP as phosphodonors. Unlike the other two isozymes, which can utilize both ATP and GTP, PI5P4Kβ exhibits a marked preference for GTP over ATP, acting as an intracellular GTP sensor that alters its kinase activity in response to physiological changes in GTP concentration. Knockout studies have demonstrated a critical role for PI5P4Kα and β in tumorigenesis, while PI5P4Kγ has been implicated in regulating immune and neural systems. Pharmacological targeting of PI5P4K holds promise for the development of new therapeutic approaches against cancer, immune dysfunction, and neurodegenerative diseases. Although several PI5P4K inhibitors have already been developed, challenges remain in PI5P4K inhibitor development, including a discrepancy between in vitro and cellular efficacy. This discrepancy is attributable to mainly three factors. (a) Most PI5P4K inhibitors were developed at low ATP levels, where these enzymes exhibit minimal activity. (b) Non-catalytic functions of PI5P4K require careful interpretation of PI5P4K depletion studies, as their scaffolding roles suppress class I PI3K signaling. (c) The lack of pharmacodynamic markers for in vivo assessment complicates efficacy assessment. To address these issues and promote the development of effective and targeted therapeutic strategies, this review provides an analytical overview of the distinct roles of individual isozymes and recent developments in PI5P4K inhibitors, emphasizing structural insights and the importance of pharmacodynamic marker identification.