Rational Design of Inhibitors of Polyamine Synthesis

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DESCRIPTION (provided by applicant): The overall goal of this program project is to discover new cancer drugs that interfere with polyamine biosynthesis. Polyamines are ubiquitous cellular components and are necessary for normal cell growth. In humans, spermine and spermidine are the main polyamines. Previous studies, including numerous clinical trials, demonstrated that inhibition of polyamine biosynthesis is a valid target for cancer chemotherapy. In the proposed research, we will focus on S-adenosylmethionine decarboxylase (AdoMetDC), spermine/spermidine N1-acetyl transferase (SSAT) and the polyamine synthases, spermidine synthase and spermine synthase, as targets for structure-based drug design. AdoMetDC is a key regulatory enzyme in polyamine biosynthesis and levels of the enzyme vary rapidly in response to the cell cycle. The first AdoMetDC inhibitor to enter clinical trials, MGBG showed unexpected toxicity. More recently, clinical trials with SAM486A have been much more encouraging. We expect even further improvements with our structure-based approach. SSAT catalyzes the rate-limiting step in polyamine catabolism. It is highly inducible and has a very short half-life. Cellular levels of SSAT are increased by compounds that prevent its degradation. Some of these compounds have shown encouraging results in clinical trials. Spermidine synthase and permine synthase catalyze the final steps of polyamine biosynthesis. Inhibitors of the polyamine synthases have not yet entered clinical trials. In this program we will use the 3-D structures and iterative structure-based drug design to develop novel inhibitors of polyamine biosynthesis. The program consists of four projects, biochemistry (Dr. Pegg), crystallography (Dr. Ealick), modeling (Dr. Guida), and synthesis (Dr. Secrist), and two cores, administrative and animal testing. The administrative core will be responsible for program integration. Once we have identified potent in vitro inhibitors, further testing against standard tumor models will be carried out in the animal core. An external committee with expertise in clinical oncology will advise us on project priorities and potential clinical trials.