The Keefer team synthesized a library of rationally designed arylated diazeniumdiolates that were screened in the Shami lab at the University of Utah for anti-AML activity using HL-60 cells. From that screen, O2-(2,4-dinitrophenyl) 1-[(4 ethoxycarbonyl)piperazin-1-yl] diazen-1-ium-1,2-diolate, or JS-K was identified as the most active agent. Through work in the Shami lab and at different institutions, JS-K has shown single agent activity in animal models of acute myeloid leukemia (AML), multiple myeloma (MM), non-small cell lung cancer, hepatocellular carcinoma, prostate cancer, glioma and Ewing’s sarcoma. JS-K was also shown to inhibit metastasis development in an orthotopic renal cell carcinoma model. JS-K synergizes with cytarabine against AML and with bortezomib against MM cells. Besides its direct cytotoxic effects, JS-K inhibits tumor angiogenesis. It also inhibits the interaction between MM cells and the bone marrow microenvironment. Mechanistically, JS-K impairs the redox status of malignant cells by depleting intracellular GSH. JS-K was also shown to upregulate the expression of CD155 on the surface of MM cells, which could sensitize them to the cytotoxic effects of immune effector cells (natural killer cells). The latter observation raises the possibility of synergy between JS-K and new cancer immunotherapy strategies. Using nanoparticles, the Shami lab has developed a clinically relevant formulation for JS-K. JS-K was well tolerated without induction of hypotension in dog toxicology studies.