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PROTAC induced-BET protein degradation exhibits potent anti-osteosarcoma activity by triggering apoptosis

Chengcheng Shi1, Huapeng Zhang2,3,4,5, Penglei Wang6

  • 1Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.

Cell Death & Disease
|October 27, 2019
PubMed

Insights

A novel proteolysis-targeting chimera (PROTAC) molecule, BETd-260, effectively degrades bromodomain and extra-terminal (BET) proteins. This targeted degradation demonstrates potent anti-osteosarcoma activity in vitro and in vivo, offering a promising new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Proteolysis-targeting chimera (PROTAC) technology offers a novel approach for targeted protein degradation in cancer therapy.
  • Bromodomain and extra-terminal (BET) proteins are epigenetic regulators implicated in osteosarcoma pathogenesis.
  • Targeting BET proteins presents a potential therapeutic strategy for osteosarcoma.

Purpose of the Study:

  • To investigate the anti-osteosarcoma activity of the BET-targeting PROTAC molecule, BETd-260, both in vitro and in vivo.
  • To evaluate the efficacy of BETd-260 in depleting BET proteins and inducing apoptosis in osteosarcoma cells.
  • To assess the therapeutic potential of BETd-260 in preclinical osteosarcoma models.

Main Methods:

  • Utilized osteosarcoma cell lines (MNNG/HOS, Saos-2, MG-63, SJSA-1) for in vitro studies.
  • Administered BETd-260 to assess protein depletion, cell viability, apoptosis, and expression of key regulatory proteins (Mcl-1, Bcl-xl, Noxa, c-Myc).
  • Evaluated in vivo efficacy using cell-derived and patient-derived osteosarcoma xenograft models in mice.

Main Results:

  • BETd-260 effectively depleted BET proteins in all tested osteosarcoma cell lines.
  • BETd-260 demonstrated significantly higher potency (>1000-fold) compared to existing BET inhibitors (HJB-97, JQ1).
  • BETd-260 induced rapid apoptosis by modulating anti-apoptotic and pro-apoptotic proteins and inhibited c-Myc, leading to profound tumor growth inhibition in vivo.

Conclusions:

  • BETd-260 exhibits potent in vitro and in vivo anti-osteosarcoma activity through targeted degradation of BET proteins.
  • BETd-260 represents a promising therapeutic agent for osteosarcoma, inducing apoptosis and inhibiting tumor growth.
  • Targeting BET proteins with PROTACs is a viable and effective strategy for osteosarcoma treatment.

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