2. Academic Validation
  3. Discovery and Optimization of Potent PROTAC Degraders of Phosphoinositide 3-Kinase with Significant in Vivo Anticancer Efficacy

Discovery and Optimization of Potent PROTAC Degraders of Phosphoinositide 3-Kinase with Significant in Vivo Anticancer Efficacy

  • J Med Chem. 2025 Jun 26;68(12):12800-12818. doi: 10.1021/acs.jmedchem.5c00679.
Shouguo Peng 1 2 3,  Qinghua Zhang 1 2 3,  Hua Tian 1 2 3,  Jingbo Zhang 1 2 3,  Jialing Deng 1 3,  Haixiang Qi 1 2 3,  Deyu Wu 1 2 3,  Tingting Du 1 3,  Kehui Zhang 1 2 3,  Junpu Ge 4,  Li Sheng 4,  Songwen Lin 1 2 3,  Ming Ji 1 3,  Heng Xu 1 2 3
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 2 Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
  • 3 CAMS Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing 100050, China.
  • 4 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD study, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 40518729 DOI: 10.1021/acs.jmedchem.5c00679
Abstract

The aberrant activation of the phosphoinositide 3-kinase (PI3K) pathway is closely linked to the progression of various cancers, highlighting its significance as a target for Cancer therapy. In contrast to conventional PI3K inhibitors, the selective degradation of PI3K protein via PROTAC technology presents a complementary therapeutic strategy. In this work, a 4-methylquinazoline based scaffold designed to bind to PI3K was conjugated with a CRBN ligand via an appropriate linker, leading to the discovery of a series of novel PI3K PROTAC degraders. Among them, degrader 12 was demonstrated to show selective degradation activity against PI3Kα, with a DC50 value of 0.08 μM. In HGC-27 and T47D Cancer cells, degrader 12 effectively degraded PI3Kα in a time- and concentration-dependent manner and potently inhibited the phosphorylation of Akt at the Ser473 site. Furthermore, with acceptable in vitro and in vivo pharmacokinetic properties, degrader 12 showed significant in vivo Anticancer efficacy in HGC-27 and DOHH2 xenograft models.

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