Double Swords in One: Novel Selective PI3 K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by Activating ERS and Inhibiting P-gp

  • J Med Chem. 2025 May 8;68(9):9446-9464. doi: 10.1021/acs.jmedchem.4c03169.
Juan Cen  1  2 ,  Ping Lu  2 ,  Chenwei Wang  2 ,  Jing Wu  2 ,  Xiaojiao Hu  2 ,  Han Zhao  2 ,  Mengyu Li  2 ,  Mingkai Luo  2 ,  Shizhen Zhao  1 ,  Xiaohui Li  1 ,  Shaofeng Duan  1  2
Affiliations
  • 1. The First Affiliated Hospital of Henan University, Kaifeng 475004, P. R. China.
  • 2. Key Laboratory of Natural Medicine and Immune Engineering, School of Pharmacy, Henan University, Kaifeng 475004, P. R. China.
PMID: 40294240 DOI: 10.1021/acs.jmedchem.4c03169
Abstract

The p110β isoform of the PI3 kinase (PI3K) family plays a key role in tumorigenesis and PTEN loss-driven multidrug resistance (MDR). Herein, we describe the design, synthesis, and structure-activity relationship studies of a series of small-molecule PI3K/110β PROTACs degraders by combining the selective inhibitor TGX221 of PI3K/110β with VHL ligands. Among them, J-6 and J-9 exhibited rapid and efficient degradation ability for the target proteins in MDR cells. Meanwhile, the expression and activity of P-glycoprotein were significantly inhibited, leading to a strong synergistic antitumor effect with adriamycin or cisplatin. Further studies confirmed that the two degraders can induce endoplasmic reticulum stress-mediated mitochondrial Apoptosis by the Akt/Bcl-2 inhibition-mediated PERK/CHOP-unfolded protein reaction. In vivo studies also verified that the two degraders inhibited the growth of MCF-7/ADM xenograft tumors with high safety. Hence, this study and further optimization of these PI3K/110β PROTAC degraders have broad prospects for the development of new Cancer therapies.

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