Development of small-molecule inhibitors that target PI3K13

Phosphatidylinositol-3 kinase (PI3K) 8, a subtype of class I PI3Ks, has an essential role in PTEN-deficient tumors and links to thrombosis, male fertility, and Fragile X syndrome. PI3K8-specific targeting therapy could be an efficacious treatment for diseases highly dependent on PI3K8, while mitigating the severe toxicity of pan-PI3K inhibitors. Achieving selectivity can be accomplished through three primary strategies, namely, binding to the induced lipophilic pocket, targeting the unique amino acid residue of PI3K8, or using atropisomerism to lock conformation. In this review, we focus on advances in the development of these 8-isoform-selective PI3K inhibitors, providing potential guidance for the further development of novel clinical candidates.