Discovery of Novel Disubstituted l-Prolinamide Derivatives as Selective PI3Kα Inhibitors for Anticancer Therapy.

PIK3CA, which encodes the p110α catalytic subunit of PI3Kα, is frequently mutated in a variety of cancers. Consequently, targeting PI3Kα using a small-molecule inhibitor represents a key therapeutic strategy for treating cancers driven by PIK3CA mutations. In recent years, several selective PI3Kα inhibitors have entered clinical investigations. In this study, to obtain an ideal PI3Kα inhibitor with high selectivity, we compared the amino acid residues within the ATP-binding pockets of four class I PI3K isoforms (α, β, γ, and δ) and observed notable differences in residues around hinge regions. Based on this, we designed and synthesized a series of novel disubstituted l-prolinamide derivatives. Biological evaluation showed that compound 26 exhibited high PI3Kα selectivity over PI3Kβ (1268-fold), PI3Kγ (350-fold), and PI3Kδ (206-fold). Further assessment of its pharmacokinetic properties and in vivo efficacy underscored the promising preclinical potential of compound 26.