Structure-Guided Design of a Highly Selective PI3Kα Inhibitor Overcoming Metabolic Dysregulation with Potent...

Targeting oncogenic PI3Kα activation in PIK3CA-mutated breast cancer remains challenging due to metabolic toxicities of existing inhibitors. To address this, we designed A32, a novel PI3Kα-selective inhibitor, via scaffold hybridization and systematic optimization. A32 exhibited exceptional potency (PI3Kα IC₅₀ = 2.5 nM) and selectivity (>400-fold over class I PI3K isoforms/mTOR). It operates through a dual mechanism: inhibiting PI3Kα kinase activity and selectively degrading the H1047R mutant p110α protein. In vitro, A32 showed robust antiproliferative activity (T47D IC₅₀ = 157 nM; MCF7 IC₅₀ = 373 nM), suppressed PI3K/AKT/mTOR signaling, induced G1 arrest, and inhibited migration. In vivo, A32 (100 mg/kg, p.o.) achieved 70.7% tumor growth inhibition in T47D xenografts, outperforming alpelisib (58.6%), without significant toxicity. Crucially, A32 (50 mg/kg) markedly reduced hyperglycemia risk versus alpelisib and displayed favorable pharmacokinetics. These findings establish A32 as a potent, selective, and metabolically safe PI3Kα inhibitor with a promising therapeutic profile.