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

Reference #: 2017-024

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Description

A newly identified SLC25A1 inhibitor that specifically targets lung cancer stem cells (CSCs) and restore ssensitivity to 51 cisplatin and to EGFR inhibitors in vitro and in animal models.

SLC25A1 is a mitochondrial protein that mediates the bidirectional flux of citrate across the mitochondrialmembrane from cytosol to the mitochondria, thus SLC25A1 is required for the proliferation of tumor cellsand 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 noteasily cross the cell membrane, owing to a negative partition coefficient and topical polar surface area suchthat milli-molar concentrations of this drug are required for the inhibition of SLC25A1.

Georgetown University researcher have through in silico homology modelling and docking experiments,identified a compound that displays strong anti-tumor activity and is capable of inducing the regression oftumors that are insensitive to canonical anti-tumor agents.

Application

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

Advantages

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

Stage of Development

Clinical trials with mitochondrial targeting drugs such as rotenone, metformin, oligomycin and CPI-613have confirmed mitochondrial respiration activity and the citrate production and transport pathway as are quirement for the growth of CSCs and therefore, valid targets with elective effects on CSCs. Researchers at Georgetown have shown the novel inhibitor reduces tumor growth as single agent and in combination therapy in patient-derived xenografts and are currently conducting studies to determine which tumor typesare most sensitive to SLC25A1 inhibitors and also to optimize future SLC25A1 inhibitor compounds.

Inventors

Maria L. Avantaggiatia

Mikell A. Paige