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The Novel Compound SIC-19 Triggers CUL4B-Mediated Ubiquitination and Degradation of SIK2

Yeqiu Zou1, Jiaqi Liu1, Shunpeng Zhu1

  • 1Department of Obstetrics and Gynecology, The First Affiliated Hospital of Soochow University, Suzhou, China.

Molecular and Cellular Biology
|May 29, 2026
PubMed

Insights

SIC-19, a novel small molecule, targets salt-inducible kinase 2 (SIK2) degradation. This mechanism involves CUL4B-DDB1 ligase, offering potential for ovarian cancer targeted therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Small-molecule inhibitors are emerging as potential cancer therapeutics.
  • Previous research identified SIC-19 as a compound inducing salt-inducible kinase 2 (SIK2) degradation, showing promise for ovarian cancer treatment.
  • The precise mechanism by which SIC-19 induces SIK2 ubiquitination remained unclear.

Purpose of the Study:

  • To elucidate the mechanism of SIC-19-induced SIK2 ubiquitination and degradation.
  • To identify the E3 ubiquitin ligase complex responsible for SIK2 ubiquitination.
  • To determine the role of specific SIK2 residues in this degradation pathway.

Main Methods:

  • Mass spectrometry to identify SIK2-interacting ubiquitin ligases.
  • Immunoprecipitation assays to confirm SIK2 and CUL4B-DDB1 interaction.
  • Western blot analysis to assess CUL4B's role in SIK2 ubiquitination and degradation.
  • Site-directed mutagenesis to identify critical SIK2 residues.

Main Results:

  • SIC-19 promotes the interaction between SIK2 and the CUL4B-DDB1 E3 ubiquitin ligase complex.
  • CUL4B is essential for SIC-19-induced SIK2 ubiquitination and subsequent degradation.
  • SIK2 ubiquitination and half-life are dose-dependent on SIC-19 and CUL4B expression.
  • Lysine 144 (K144) in SIK2 was identified as a critical residue for degradation, impacting cancer cell proliferation and migration.

Conclusions:

  • SIC-19 induces SIK2 degradation via a novel CUL4B-dependent ubiquitination pathway.
  • This mechanism highlights SIC-19's potential as a targeted therapeutic agent for cancers driven by SIK2.
  • Targeting SIK2 degradation represents a promising strategy for ovarian cancer therapy.
Keywords:
CUL4BDDB1SIC-19SIK2lysine144ovarian cancerubiquitin

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