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Small-molecule inhibitors targeting Polycomb repressive complex 1 RING domain

Shirish Shukla1, Weijiang Ying1, Felicia Gray1

  • 1Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Nature Chemical Biology
|June 22, 2021
PubMed

Insights

Researchers developed small-molecule inhibitors targeting Polycomb Repressive Complex 1 (PRC1) by binding to the RING1B-BMI1 complex. These inhibitors block H2A ubiquitination and show potential in treating acute myeloid leukemia (AML).

Area of Science:

  • Chromatin biology
  • Epigenetics
  • Cancer research

Background:

  • Polycomb Repressive Complex 1 (PRC1) is crucial for maintaining repressed chromatin states via histone H2A monoubiquitination.
  • PRC1's role in cancer necessitates targeted small-molecule inhibitors with clear mechanisms of action.

Purpose of the Study:

  • To develop and characterize small molecules that directly inhibit the E3 ligase activity of the PRC1 RING1B-BMI1 complex.
  • To investigate the therapeutic potential of PRC1 inhibitors in leukemia models.

Main Methods:

  • Development of small-molecule inhibitors targeting the RING1B-BMI1 heterodimer.
  • Structural studies to elucidate inhibitor binding mechanisms.
  • Assessment of inhibitor efficacy in cellular assays and primary acute myeloid leukemia (AML) samples.

Main Results:

  • Compounds were identified that bind to RING1B, inducing a hydrophobic pocket and blocking PRC1 chromatin association.
  • The inhibitor RB-3 effectively decreased global H2A ubiquitination levels.
  • RB-3 induced cellular differentiation in leukemia cell lines and primary AML samples.

Conclusions:

  • Targeting the PRC1 RING domain with small molecules is a viable therapeutic strategy.
  • RB-3 is a potent chemical tool for studying PRC1 function and exploring its therapeutic applications in cancer, particularly AML.

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