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A Strategy to Identify Compounds that Affect Cell Growth and Survival in Cultured Mammalian Cells at Low-to-Moderate Throughput
Published on: September 22, 2019
Structure-guided identification of small molecules potentially able to modulate GDF15 activity
Antonio Chiariello1, Lorenzo Lenti2, Lorenzo Trofarello1
1Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40126, Bologna, Italy.
Scientific Reports
|May 7, 2026
Summary
Small organic molecules (SOMs) can inhibit Growth Differentiation Factor 15 (GDF15). A novel SOM, SOM D, disrupted GDF15 dimers and modulated downstream signaling in cancer cells, showing therapeutic potential.
Area of Science:
- Biochemistry
- Molecular Biology
- Drug Discovery
Background:
- Growth Differentiation Factor 15 (GDF15) is implicated in pathological conditions like cancer cachexia.
- Current GDF15 inhibitors include monoclonal antibodies and peptide antagonists.
- The potential of small organic molecules (SOMs) to target GDF15 remains unexplored.
Purpose of the Study:
- To identify SOMs capable of inhibiting GDF15 activity.
- To evaluate the efficacy of identified SOMs in vitro and in cellular models.
- To assess the therapeutic potential of SOMs as GDF15 inhibitors.
Main Methods:
- Structure-based in silico screening of a compound library against GDF15.
- In vitro testing of top-ranking SOMs in acellular systems.
- In vitro testing in normal (dermal fibroblasts) and cancer (ovarian) cells with varying GDF15 expression.
Main Results:
- A dioxoimidazolidin derivative (SOM D) showed promise in inhibiting GDF15.
- SOM D disrupted GDF15 dimer stability and GDF15-GFRAL interaction.
- SOM D modulated downstream GDF15 signaling (IL-6, NF-κB) in ovarian cancer cells.
Conclusions:
- GDF15 activity can be modulated by SOMs.
- SOM D demonstrates potential as a GDF15 inhibitor.
- Further optimization and studies are warranted to assess therapeutic potential.
