Anthrax Lethal Factor (LF) is a protein toxin introduced into the cells of mammalian hosts during infection by the bacterium Bacillus anthracis. The toxemia due to LF results from disruption of intracellular signaling pathways mediated by the MAPKKs resulting in cell death and immunosuppression. Left unchecked, continued growth of the bacteria and release of toxin leads to sepsis, shock, and ends with death of the host. While exposure to this pathogen is limited in nature, the lethality of anthrax spores when used as a bioterrorism weapon was clearly demonstrated in the 2001 attacks through the US mail. Novel therapeutics capable of acting as an antidote to the toxic effects of LF are needed to combat this real threat. Existing treatment methods such as antibiotics, vaccines, and biologic therapies currently in development, suffer from significant drawbacks. Common to each is their inability to protect cells from the direct effects of LF, rescue the host during late-stage infection, and vulnerability to 'next generation' genetically modified LF weapons. Directly targeting LF activity alone, or in combination with current therapies, would provide the best protection for the general population in the event of a large scale bioterrorism anthrax attack. Recent work at PanThera has led to the identification of small molecule LF inhibitors which provide 100% survivability in an animal model of anthrax lethal toxin (LT). This early proof of concept study clearly demonstrates that the intrinsic structure of our current lead series can function in vivo as an antidote to LT. The work proposed in this UO1 application will build on PanThera's expert knowledge of LF as a drug target. By employing medicinal chemistry guided by a screening cascade designed to optimize the physicochemical and pharmacokinetic properties of our current lead series, the ADMET profile of potent LF inhibitors will be refined with the goal of identifying orally bioavailable preclinical candidates that are safe and demonstrate in vivo efficacy in a post-exposure animal model of anthrax lethal factor intoxication. Brief Narrative: The lethality of anthrax spores when used as a bioterrorism weapon was clearly demonstrated in the 2001 attacks through the US mail. The goal of this research is to identify a safe and effective drug capable of acting as an antidote to the toxic effects due to anthrax exposure to combat this continuing and real threat.