IODVA1, a Guanidinobenzimidazole Derivative with in vivo Activity Against Ras-Driven Cancer Models

Abstract

We report the synthesis and preliminary characterization of IODVA1, a potent small molecule that is active in xenograft mouse models of Ras-driven lung and breast cancers. In an effort to inhibit oncogenic Ras signaling, we combined in silico screening with inhibition of proliferation and colony formation of Ras-driven cells. NSC124205 fulfilled all criteria. HPLC analysis revealed that NSC124205 was a mixture of at least three compounds, from which IODVA1 was determined to be the active component. IODVA1 decreased 2D proliferation, 3D spheroid formation, spreading and lamellipodia formation in breast cancer cells. IODVA1 significantly impaired xenograft tumor growth of Ras-driven cancer cells with no observable toxicity. Immuno-histochemistry analysis of tumor sections suggests that cell death occurs by increased apoptosis. Our data suggest that IODVA1 targets a node used by Ras to regulate cell survival, spreading, and movement including lamellipodia formation. Therefore, IODVA1 holds promise as an anti-tumor therapeutic agent.

Keywords: Drug Screening, drug discovery, Small Molecule Inhibitor, Medicinal chemistry, Rat-Driven Cancer, Breast Cancer, lung cancer, Lamellipodia, Actin.