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Discovery of the First Potent DYRK2 Proteolysis Targeting Chimera Degraders

Jian Chen1, Wentao Zhu1, Wenqian Zhang1

  • 1School of Chemistry, Sun Yat-sen University, Guangzhou 510275, China.

ACS Medicinal Chemistry Letters
|May 15, 2024
PubMed

Insights

Researchers developed the first proteolysis-targeting chimeras (PROTACs) to degrade Dual-specificity tyrosine phosphorylation-regulated kinase 2 (DYRK2), a cancer target. The compound CP134 effectively reduced DYRK2 levels via the ubiquitin-proteasome system.

Area of Science:

  • Oncology
  • Molecular Biology
  • Medicinal Chemistry

Background:

  • DYRK2 is an oncogenic driver in multiple cancers, making it a key therapeutic target.
  • Existing DYRK2 inhibitors are available, but no degraders have been developed.
  • Targeting protein degradation offers a novel therapeutic strategy.

Purpose of the Study:

  • To design and synthesize the first series of PROTACs targeting DYRK2.
  • To evaluate the efficacy of these PROTACs in degrading DYRK2.
  • To investigate the mechanism of action for DYRK2 degradation.

Main Methods:

  • PROTACs were designed using curcumin analogs as warheads.
  • Degradation assays were performed to assess intracellular DYRK2 levels.
  • Mechanism of action studies utilized the ubiquitin-proteasome system.

Main Results:

  • The compound CP134 effectively degraded intracellular DYRK2 with a DC50 of 1.607 μM.
  • CP134-induced degradation of DYRK2 occurred via the ubiquitin-proteasome pathway.
  • This study presents the first potent DYRK2 degrader.

Conclusions:

  • CP134 is the first identified potent degrader of DYRK2.
  • CP134 serves as a valuable chemical tool for exploring DYRK2's therapeutic potential.
  • This work expands the application of PROTACs to new substrate targets.

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