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PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28

Aseel Kashkush1, Judith Furth-Lavi1, Jiri Hodon1

  • 1The Institute for Drug Research of the School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Hadassah-Ein Kerem, Jerusalem, 91120, Israel.

Macromolecular Bioscience
|November 22, 2024
PubMed

Insights

Targeting the oncogenic protein Lin28 with small molecule degraders, specifically molecular glues, effectively inhibits cancer progression by restoring tumor suppressor microRNA let-7 activity.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Protein-RNA interactions are vital for gene regulation, and their disruption is implicated in diseases like cancer.
  • The RNA-binding protein Lin28 promotes cancer by inhibiting the tumor suppressor microRNA let-7.
  • Targeting Lin28 offers a therapeutic strategy for cancer treatment.

Purpose of the Study:

  • To develop novel small molecule strategies for degrading the oncogenic protein Lin28.
  • To compare the efficacy of Proteolysis Targeting Chimera (PROTAC) and molecular glue approaches for Lin28 degradation.
  • To assess the impact of Lin28 degradation on cancer cellular phenotypes.

Main Methods:

  • Design and synthesis of PROTAC bifunctional molecules targeting Lin28.
  • Development of molecular glues for targeted Lin28 degradation.
  • In vitro and cellular assays to evaluate Lin28 degradation and functional consequences.

Main Results:

  • Both PROTAC and molecular glue strategies successfully reduced Lin28 levels in cells.
  • Degradation of Lin28 by both methods alleviated cancer-associated cellular phenotypes.
  • The molecular glue approach demonstrated superior potency and efficiency compared to PROTAC.

Conclusions:

  • Targeted degradation of Lin28 using small molecules, particularly molecular glues, is a promising therapeutic strategy for cancers driven by Lin28 overexpression.
  • Molecular glues offer an efficient platform for modulating RNA-binding protein activity and treating related diseases.
  • This study highlights the potential of innovative small molecule degraders in RNA-based therapeutics.
Keywords:
PROTACRNA binding protein (RBP)microRNAmolecular gluetargeted degradation

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