Related Experiment Video
Updated: Jan 14, 2026
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Efficient identification of new small molecules targeting succinate dehydrogenase in non-small cell lung cancer
Luis Silva1, Nicholas Skiados1, Nikitha Murugavel1
1Department of Cancer Division, College of Medicine, Burnett School of Biomedical Sciences, University of Central Florida, 6900 Lake Nona Blvd, Orlando, FL, 32827, USA.
Background:
Lung cancer treatment efficacy remains a challenge due to limited therapeutic targets. Succinate dehydrogenase (SDH) enzyme, a crucial enzyme linking the citric acid cycle and the electron transport chain, is implicated in cancer metabolism. While existing compounds target metabolic diseases in vitro, SDH-targeted therapy for lung cancer remains elusive.
Methods:
We assessed SDH expression levels in non-small cell lung (NSCLC) tissues and cell lines. Leveraging AtomNet® technology for compound identification, coupled with mitochondria- and cell-based enzyme activity assays, we discovered new SDH inhibitors. Using 2D monolayer, 3D organoid culture, and assays for cell viability, migration, mitochondrial reactive oxygen species, oxygen consumption rate, succinate accumulation, and apoptosis, we elucidated their mechanism targeting lung malignancy.
Results:
SDH subunits were found to be overexpressed in NSCLC tissues compared to tumor-adjacent normal tissues. Two new SDH inhibitors were identified from 96 predicted candidates. Cellular thermal shift assay confirmed direct binding of these small molecules to SDH subunits in lung cancer cells. Mechanistically, treatment increased cellular and mitochondrial reactive oxygen species, succinate accumulation, and induced apoptosis by damaging mitochondria and DNA, while modulating SDH protein expression. Functionally, these molecules reduced growth, migration, and 3D organoid formation in lung cancer cell lines in vitro, both short and long term.
Conclusions:
Our SDH inhibitors halt tumor growth and migration by targeting key substrate binding sites, showing superior efficacy over existing small molecule antagonists. They also modulate SDH protein expression, suggesting a promising dual-targeting strategy for cancer therapy. This study sheds light on SDH function in cancer-related metabolic dysfunction and underscores the potential of SDH modulation as a therapeutic strategy for lung cancer and beyond.
Insights
New succinate dehydrogenase (SDH) inhibitors show promise for lung cancer therapy. These compounds target SDH enzyme activity, halting tumor growth and migration by disrupting cancer metabolism.
Area of Science:
- Biochemistry
- Oncology
- Drug Discovery
Background:
- Lung cancer treatment faces challenges due to limited therapeutic targets.
- Succinate dehydrogenase (SDH) is implicated in cancer metabolism but lacks targeted therapies for lung cancer.
- Existing metabolic disease compounds are not effective for SDH-targeted lung cancer therapy.
Purpose of the Study:
- To identify and characterize novel succinate dehydrogenase (SDH) inhibitors for non-small cell lung cancer (NSCLC) therapy.
- To elucidate the mechanism of action of SDH inhibitors in lung cancer cells.
- To evaluate the efficacy of SDH inhibitors in preclinical lung cancer models.
Main Methods:
- Assessed SDH expression in NSCLC tissues and cell lines.
- Utilized AtomNet® technology for compound identification and in vitro enzyme activity assays.
- Conducted cell viability, migration, ROS, OCR, succinate, and apoptosis assays in 2D and 3D lung cancer models.
Main Results:
- SDH subunits were overexpressed in NSCLC tissues.
- Two novel SDH inhibitors were identified and confirmed to bind SDH subunits.
- Inhibitors increased ROS and succinate, induced apoptosis, and reduced tumor growth, migration, and organoid formation in vitro.
Conclusions:
- Novel SDH inhibitors effectively halt lung cancer growth and migration by targeting key binding sites.
- These inhibitors demonstrate superior efficacy and a promising dual-targeting strategy by modulating SDH protein expression.
- SDH modulation presents a potential therapeutic strategy for lung cancer and other malignancies.
