Beyond PI3Ks: targeting phosphoinositide kinases in disease

The potential of therapeutically targeting phosphoinositide kinases (PIKs) beyond the class I PI3Ks is increasingly being realized. Here, Burke et al. describe the structure, function, regulation and roles in disease of all clinically relevant PIKs outside of the class I PI3Ks, assessing potent and specific small-molecule inhibitors in development. Lipid phosphoinositides are master regulators of almost all aspects of a cell's life and death and are generated by the tightly regulated activity of phosphoinositide kinases. Although extensive efforts have focused on drugging class I phosphoinositide 3-kinases (PI3Ks), recent years have revealed opportunities for targeting almost all phosphoinositide kinases in human diseases, including cancer, immunodeficiencies, viral infection and neurodegenerative disease. This has led to widespread efforts in the clinical development of potent and selective inhibitors of phosphoinositide kinases. This Review summarizes our current understanding of the molecular basis for the involvement of phosphoinositide kinases in disease and assesses the preclinical and clinical development of phosphoinositide kinase inhibitors.