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Structure-Activity Relationship Analysis of YM155 for Inducing Selective Cell Death of Human Pluripotent Stem Cells

Young-Hyun Go1, Changjin Lim2, Ho-Chang Jeong1

  • 1Department of Life Sciences, College of Natural Sciences, Sogang University, Seoul, South Korea.

Frontiers in Chemistry
|June 4, 2019
PubMed

Insights

Researchers synthesized YM155 analogs to eliminate undifferentiated human pluripotent stem cells (hPSCs) for safer cell therapy. A pyrazine ring

Area of Science:

  • Stem cell biology
  • Regenerative medicine
  • Drug discovery

Background:

  • Human pluripotent stem cells (hPSCs) hold great promise for regenerative medicine.
  • A major hurdle for hPSC therapy is their tumorigenic potential, leading to teratoma formation.
  • Stemotoxics are small molecules designed to eliminate undifferentiated hPSCs, enabling tumor-free cell therapy.

Purpose of the Study:

  • To synthesize and evaluate YM155 analogs for stemotoxic activity against hPSCs.
  • To identify structural features critical for stemotoxic efficacy.
  • To elucidate the mechanism of YM155 uptake and activity in hPSCs.

Main Methods:

  • Synthesis of 26 analogs based on the YM155 chemical structure.
  • Testing of analogs for stemotoxic activity on human embryonic stem cells (hESCs) and induced PSCs (iPSCs).
  • Investigation of the role of the solute carrier family 35 member F2 (SLC35F2) protein in YM155 activity.

Main Results:

  • A hydrogen bond acceptor in the pyrazine ring of YM155 derivatives was found to be essential for stemotoxic activity.
  • Stemotoxic activity was completely abolished in hESCs lacking SLC35F2.
  • This suggests that SLC35F2 is critical for the cellular uptake of YM155.

Conclusions:

  • The nitrogen atoms in the pyrazine ring of YM155 analogs are crucial for stemotoxic activity.
  • Hydrogen bonding interactions between the pyrazine ring and the SLC35F2 protein mediate YM155 entry into hPSCs.
  • Targeting SLC35F2 could be a strategy to enhance the efficacy of stemotoxic agents for cell therapy.
Keywords:
SAR (structure-activity relationship)YM155human pluripotent stem cellsnaphthoquinone imidazoliumstemotoxicsteratoma

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