2. Academic Validation
  3. Rational Design of Potent and Orally Efficacious PI3Kα/δ Degrader for PIK3CA Mutant Breast Cancer without Hyperglycemic Liability

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

  • J Med Chem. 2026 Mar 8. doi: 10.1021/acs.jmedchem.5c03368.
Yi Hou 1 2 3,  Xinqing Zheng 1 2 3,  Yiwen Zhang 1 2 3,  Hao Shen 1 2 3,  Chenxun Kang 1 2 3,  Han Qin 1 2 3,  Shuyang Cao 1 2 3,  Yasheng Zhu 1 2 3,  Xiao Wang 1 2 3,  Chengliang Sun 1 2 3,  Jiayu Ding 1 2 3,  Zhongrui Shi 1 2 3,  Liping Wang 1 2 3,  Kai Yuan 1 2 3,  Wenjian Min 1 2 3,  Peng Yang 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Jiangsu Provincial Key Laboratory of Targetome and Innovative Drugs Medicines, China Pharmaceutical University, Nanjing 211198, China.
  • 2 Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
  • 3 Institute of Innovative Drug, China Pharmaceutical University, Nanjing 211198, China.
PMID: 41796700 DOI: 10.1021/acs.jmedchem.5c03368
Abstract

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.

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