Structure-Guided Design of a Highly Selective PI3Kα Inhibitor Overcoming Metabolic Dysregulation with Potent Anti-breast Cancer Efficacy

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.