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 D5 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. D5 demonstrated potent sensitivity toward tumor cell lines
driven by the oncogenic PIK3CA H1047R mutation. Orally
administered D5 (40 mg/kg) significantly inhibited tumor
growth (65% TGI) in xenograft models without inducing metabolic dysregulation. D5 may offer a therapeutic option for human breast cancer
harboring the PIK3CA H1047R mutation.