Acute myeloid leukemia (AML) is a blood cancer with the poorest prognosis at approximately 20%. Thus, novel anticancer agents to combat this disease are needed. This proposal uses a pro-drug strategy to design anticancer agents where an AML-cell specific phenotype is harnessed to activate the agent. It is known that AML cancer cells possess elevated reactive oxygen species. Reactive oxygen species benefit cancer cells by enhancing angiogenesis and activating growth cascades. This proposal seeks to translate these biochemical findings into useful anticancer agents. The long-term goal of the project is to design novel molecular entities for use as AML anti-cancer agents. The overall objective of this application, which is the next step toward attainment of our long-term goal, is to identify a soluble and general metabolism-resistant agent capable of eradicating AML cancer cells in vivo. The hypothesis is that agents protected at a key position will degrade with a half-life of 4-5 hours allowing in vivo AML cell eradication. The hypothesis has been formulated based on preliminary data that demonstrates ROS-specific activation, verifies the precise DNA lesion formed by these pro-drugs, a promising increase in AML-mouse survival, and PK measurements. To accomplish the goals, an interdisciplinary team of a chemical biologist (to synthesize and biochemically evaluate agents) and a cancer biologist (to characterize the anticancer potential of the agents in vivo) has been forged. The testing of the central hypothesis will occur through one aim. (1) Identify an in vivo selective agent with appropriate pharmacokinetic properties. In this proposal strategic placement of specific groups on the lead agent will occur. The novel functionalities impart resistance to metabolic phase 1 and 2 reactions as well as albumin sequestration. These functionalities slowly hydrolyze to give sustained concentrations of the lead compound in vivo. In vitro, quantification of hydrolysis (enzymatic and intrinsic), plasma stability, metabolic degradation by liver microsomes, and activation. These properties will be quantified as t1/2, Vmax and Km. In vivo examination of agent half-life and concentration-dependent AML cell death via FACS. The outcomes of the aims are as follows. First, identifying an agent with a strong pharmacokinetics (PK) profile will show that ROS-agents can survive in vivo and that these new designs are potentially clinically relevant anti-cancer agents with good therapeutic windows. Second, showing in vivo AML cell death will be an important and exciting outcome since it will positively position the team to achieve the longer-term goal of in vivo efficacy. Positive results will show a new molecular entity with a nove mechanism of action that can be used to improve prognosis in AML and potentially other cancers. This proposal is expected to serve as the basis for a subsequent R01 submission that will analyze continued medicinal chemistry efforts, ADME, fully evaluate efficacy, and establish the biochemical mechanism of the agents to complete pre-clinical experiments.
The proposed research is relevant to public health because it describes the design and evaluation of novel anticancer agents that work in mice. This project, if successful, will establish a possible strategy and agent for use in the treatment of acute myeloid leukemia. The prognosis for patients with this cancer can be improved by the design of better anticancer agents.
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