Rational Design of Potent and Orally Efficacious PI3Kα/δ Degrader for PIK3CA Mutant Breast Cancer without Hyperglycemic Liability

Although PROTAC technology has been reported for targeted PI3K degradation in cancer therapy, the rational design of isoform-selective PI3K PROTACs and their safety profiles compared to their cognate small-molecule inhibitors remain unexplored. We have reported a structure-guided PROTAC development strategy for selective PI3Kα/δ degradation. This approach enabled the rational design of copanlisib-based PROTACs, with top compound <b>D5</b> achieving catalytic degradation efficiency (PI3Kα DC₅₀ = 0.05 nM in T47D cells), >10,000-fold degradation selectivity over the PI3Kβ and PI3Kγ isoforms and minimal off-target effects across >7000 profiled proteins. <b>D5</b> demonstrated potent sensitivity toward tumor cell lines driven by the oncogenic <i>PIK3CA H1047R</i> mutation. Orally administered <b>D5</b> (40 mg/kg) significantly inhibited tumor growth (65% TGI) in xenograft models without inducing metabolic dysregulation. <b>D5</b> may offer a therapeutic option for human breast cancer harboring the <i>PIK3CA H1047R</i> mutation.