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Double Swords in One: Novel Selective PI3K/110β PROTAC Degraders for the Treatment of Multidrug-Resistant Cancer by

Juan Cen1,2, Ping Lu2, Chenwei Wang2

  • 1The First Affiliated Hospital of Henan University, Kaifeng 475004, P. R. China.

Journal of Medicinal Chemistry
|April 28, 2025
PubMed

Insights

New PROTAC degraders targeting PI3K-p110β show promise in combating multidrug resistance and cancer. These molecules effectively degrade target proteins, inhibit P-glycoprotein, and induce apoptosis, leading to significant tumor growth inhibition in vivo.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • The p110β isoform of phosphoinositide 3-kinase (PI3K) is implicated in cancer development and multidrug resistance (MDR) associated with PTEN loss.
  • Targeting PI3K-p110β offers a potential therapeutic strategy for overcoming treatment resistance in cancer.

Purpose of the Study:

  • To design, synthesize, and evaluate novel PI3K-p110β PROTAC degraders for cancer therapy.
  • To investigate the mechanism of action and in vivo efficacy of these degraders.

Main Methods:

  • Structure-activity relationship (SAR) studies were conducted on PI3K-p110β PROTAC degraders.
  • Degradation of target proteins and inhibition of P-glycoprotein were assessed in MDR cells.
  • Apoptosis pathways, including endoplasmic reticulum stress and mitochondrial pathways, were analyzed.
  • In vivo efficacy and safety were evaluated using a xenograft tumor model.

Main Results:

  • Compounds J-6 and J-9 demonstrated efficient degradation of PI3K-p110β in MDR cells.
  • Significant inhibition of P-glycoprotein expression and activity was observed.
  • Synergistic antitumor effects were achieved when combined with adriamycin or cisplatin.
  • Degraders induced apoptosis via AKT/Bcl-2 inhibition-mediated PERK/CHOP pathway activation.
  • In vivo studies showed potent inhibition of tumor growth in MCF-7/ADM xenografts with good safety.

Conclusions:

  • The developed PI3K-p110β PROTAC degraders, J-6 and J-9, are effective in overcoming MDR and exhibit significant antitumor activity.
  • These PROTACs induce apoptosis through a specific molecular mechanism involving ER stress and mitochondrial pathways.
  • Further optimization holds promise for developing new cancer therapeutics with broad applicability.

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