Abstract: Inhibitors of the MAPK pathway, including MEK-directed proteases and small molecule inhibitors, are cytotoxic to human melanoma cells in vitro and in vivo via apoptotic mechanisms. These compounds are used to kill melanoma cells and to treat subjects with melanoma, either alone or in combination with other therapeutic modalities.

Abstract: A series of mutants of Anthrax lethal factor (LF) are disclosed which define a conformational epitope or region of the molecule that interacts with the LF target, the MEK enzyme. Such mutants or variants, and nucleic acids encoding them are disclosed. The knowledge of such binding, separate from recognition of MEK by the protease active site of LF, serves as the basis for novel screening assays for discovery of inhibitors of this additional form of LF-MEK binding which is necessary for ultimate proteolysis and toxicity. The nontoxic LF mutants are useful as immunogenic compositions for generating antibodies and a state of immunity specific for the LF component of a B. arithracis infection or exposure otherwise to the anthrax lethal toxin.

Abstract: A method for inhibiting cell angiogenesis comprises contacting cells associated with undesired angiogenesis with an effective amount of an inhibitor of MEK or of an enzyme that is a member of the MAPK family. MEK inhibitors include MEK-directed proteases such as Bacillus anthracis lethal factor or a functional derivative thereof. Organic small molecule inhibitors of MEK include PD98059, U0126 and PD184352. The above contacting may be performed in vivo, in a human or other mammalian subject. Also included is a method to treat a mammalian subject having a disease or condition associated with undesired angiogenesis or neovascularization, comprising administering to the subject an effective amount of a pharmaceutical composition that comprises an inhibitor of MEK or of an enzyme that is a member of the MAPK family, as noted above, and pharmaceutically acceptable carrier or excipient.