New Small Molecules for Targeting Succinate Dehydrogenase

Abstract

The University of Central Florida invention identifies four new small molecules that can effectively modulate succinate dehydrogenase (SDH) enzymatic activity, degrade protein abundance, and generate cytotoxic reactive oxygen species (ROS). The discovery will provide a new therapeutic approach to target lung and other types of cancers. The data supports that these molecules are more effective in inhibiting lung cancer colony formation than the known SDH inhibitor dimethyl malonate (DMM).

Efficient lung cancer treatment remains challenging due to the lack of therapeutic targets. The succinate dehydrogenase (SDH) enzyme plays a critical metabolic role as an intermediate between the citric acid cycle and the electron transport chain associated with the cancer disease state. Although several existing compounds have been applied to target metabolic diseases in vitro, modulating SDH for lung cancer treatment is still elusive.

Technical Details: UCF researchers identified the four new small molecules from 96 predicted candidates by integrating in-silico compound design with mitochondria- and cell-based enzyme activity assays. The cellular thermal shift assay confirmed that the small molecules bind directly to SDH subunits in lung cancer cells. Mechanistically, treatment with the small molecules increased reactive oxygen species and DNA damage in lung cancer cell lines. Functionally, the small molecules reduced short-term and long-term malignant growth of lung cancer cell lines in vitro.

Benefit

Market Application