Discovery and Validation of novel inhibitor compounds of the mitochondrial carrier SLC25A1 as anti-tumor agents

OVERVIEW

Researchers at Georgetown University have developed methods for treating or preventing cancer. The approach involves administering a specific amount of a SLC25A1 inhibitor. A newly identified SLC25A1 inhibitor has been discovered to target lung cancer stem cells (CSCs) and restore sensitivity to cisplatin and EGFR inhibitors, bothin vitroand in animal models. Researchers at Georgetown University utilized in silico homology modeling and docking experiments to identify this compound, which demonstrates potent anti-tumor activity and the ability to induce regression in tumors resistant to conventional anti-tumor agents.

BACKGROUND

SLC25A1 is a mitochondrial protein that mediates the bidirectional flux of citrate across the mitochondrial membrane from the cytosol to the mitochondria. Thus, SLC25A1 is required for the proliferation of tumor cells and particularly for the expansion of the cancer stem cell population in lung cancer. Inhibition of SLC25A1 hampers tumor growth in vivo; however, the best known SLC25A1 inhibitor – BTA, does not easily cross the cell membrane, owing to a negative partition coefficient and topical polar surface area such that milli-molar concentrations of this drug are required for the inhibition of SLC25A1.

Benefit

• Therapy that specifically targets hard-to-treat cancer stem cells
• Works on tumors that are particularly insensitive to conventional anti-tumor agents
• SLC25A1 inhibitor that can be used in combination with conventional anti-tumor agents to provide a therapeutic benefit
• SLC25A1 inhibitors might render tumors with a broad range of mutational landscapes, clinically manageable

Market Application

• Anti-tumor agent that specifically targets CSCs wherein SLC25A1 is over-expressed.

Publications

• US Patent Appln.16/636,226
• The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond. Biomolecules 2021, 11(2), 141;https://doi.org/10.3390/biom11020141