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Chemical induction of the interaction between AIMP2-DX2 and Siah1 to enhance ubiquitination

Dae Gyu Kim1, Minkyoung Kim2, Ja-Il Goo3

  • 1Medicinal Bioconvergence Research Center, Institute for Artificial Intelligence and Biomedical Research, College of Pharmacy & College of Medicine, Gangnam Severance Hospital, Yonsei University, Incheon 21983, Republic of Korea; Department of Yuhan Biotechnology, School of Health & Wellness Services, Yuhan University, Bucheon 14780, Republic of Korea.

Cell Chemical Biology
|September 11, 2024
PubMed

Insights

A novel compound, SDL01, targets the oncogenic AIMP2-DX2 variant by enhancing its interaction with Siah1. This promotes DX2 degradation, offering a new strategy to inhibit cancer development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • AIMP2-DX2 (DX2) is an oncogenic variant of AIMP2 implicated in cancer progression.
  • DX2 promotes tumorigenesis through interactions with various cancer-related factors.
  • Reducing DX2 levels is a potential strategy for cancer inhibition.

Purpose of the Study:

  • To identify compounds that can reduce DX2 levels.
  • To investigate the mechanism by which SDL01 affects DX2.
  • To explore the modulation of protein-protein interactions (PPIs) for therapeutic benefit.

Main Methods:

  • Identification of SDL01 as a compound enhancing DX2 degradation.
  • Biochemical assays to study the interaction between DX2, Siah1, and SDL01.
  • Analysis of SDL01 binding site and conformational changes induced in DX2.

Main Results:

  • SDL01 enhances the interaction between DX2 and Siah1.
  • This enhancement facilitates ubiquitin-dependent degradation of DX2.
  • SDL01 binds to DX2, inducing conformational changes that stabilize the DX2-Siah1 interaction.

Conclusions:

  • Chemically induced conformational changes can modulate protein-protein interactions.
  • SDL01 represents a potential therapeutic agent by targeting DX2 degradation.
  • Targeting oncogenic protein variants through PPI modulation is a viable cancer treatment strategy.
Keywords:
AIMP2-DX2Siah1allosteric modulationand molecular dockingsmall moleculeubiquitination

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