The Ras protein is a small GTPase involved in key cell signaling pathways regulating cell growth, differentiation, and programmed cell death.   Mutations of the Ras protein occur in 30% of all cancers and are difficult to target due to the complex network of upstream and downstream regulators.  A high priority has been to identify compounds that are Ras-selectively lethal (RSL) while ineffective against healthy cells or cells that are Ras wild type.  Several RSL compounds, such as Erastin, Oncrasin-1, and Lanperisone, have been identified and kill cancer cells through a unique mechanism of action called ferroptosis.  Ferroptosis is a non-apoptotic form of cell death that utilizes iron to increase the intracellular levels of reactive oxygen species (ROS).  We have synthesized and identified a new class of small molecule anticancer agents that exhibit a ferroptotic mechanism of action.  The synthesis and biological evaluation of the ferroptotic therapeutics will be presented.

Ferroptotic small molecules for the treatment of <i>Ras</i>-mutated cancers

248th National Meeting (2014)

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Ferroptotic small molecules for the treatment of Ras-mutated cancers