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    Awarded Grants
    Structure-Based Inhibitor Design for a Cancer Target in De Novo Purine Biosynthesis Pathway

    Scientific Abstract:
    Structure-based inhibitor design for a cancer target in de novo purine biosynthesis pathway Scientific Abstract The de novo purine biosynthesis pathway includes ten enzymatic reactions that catalyze the conversion of 5-phosphoribosyl-1-pyrophosphate to inosine monophosphate (IMP), the precursor of purine nucleotides that are indispensable for normal cells, as well as the proliferation of tumor cells. Whereas tumor cells require large amount of nucleic acids, and rely more heavily on the de novo purine biosynthesis pathway, normal cells mainly utilize the salvage pathway from recycled nucleotides. Therefore, the purine biosynthesis pathway has been characterized as a viable target for anti-neoplastic intervention. Of the ten enzymes that catalyze the reactions in de novo purine biosynthesis pathway, aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase (AICAR Tfase) /IMP cyclohydrolase (IMPCH) (ATIC) is the second folate-dependent enzyme in the pathway. ATIC is a bifunctional enzyme that is responsible for the penultimate and final reactions of this pathway, and has emerged a prime target for antitumor drug development. Inhibitors of this enzyme would selectively block the purine biosynthesis pathway and inhibit cancer cell proliferation. The active sites of both avian and human ATIC have been well characterized and, hence, provide a template for the design of small molecule inhibitors. Development of potential therapeutic compounds has focused on the design of folate-based inhibitors. However, as folates are involved in many cellular processes, the toxic side effects of the folate-based drugs are significant. Thus, the design of potent small molecules with novel structures that specifically target ATIC is an attractive approach to development entirely new chemotherapies for treatment of various cancers, such as leukemia and breast cancer. We hypothesize that inhibitors with novel scaffolds other than folate will selectively inhibit ATIC activity and, hence, deplete the nucleotide reservoir essential for tumor cell growth. Structure-based drug design will be used to identify and develop novel small molecule inhibitors as a new class of antitumor drugs for breast cancer. Novel ATIC inhibitors will be identified through virtual ligand screening of a chemical database. In addition, substrate-based inhibitors will be designed through specific modification of the substrate structure. Enzymatic inhibition assays will be carried out to evaluate the efficacy of these compounds. Structures of ATIC complexed with promising inhibitors will provide key interactions between the protein active site residues and the inhibitors. The structural information will be invaluable for iterations of lead compound optimization through chemical synthesis, enzymatic inhibition and cytotoxicity evaluation. The identification of novel, non-folate based inhibitors should eventually lead to discovery of new, more efficacious antitumor drugs with less adverse side effects for breast cancer treatment.

    Lay Abstract:
    Structure-based inhibitor design for a cancer target in de novo purine biosynthesis pathway The de novo purine and pyrimidine biosynthesis pathways are utilized by virtually all organisms to produce the purine and pyrimidine nucleotides, the precursory products of RNAs and DNAs that are indispensable for cellular proliferation. Tumor cells, unlike normal cells, proliferate at an uncontrolled rate, which demands large amount of RNA and DNA. An interesting prior observation revealed that tumor cells rely more heavily on elevated de novo biosynthesis, while normal cells can take advantage of the salvage pathway, where recycled nucleotides are utilized. Inhibitors designed specifically to target de novo biosynthesis pathways will deplete the nucleotide reservoir required from tumor cell growth, while normal cells should maintain their status via salvage pathways. Folic acid and its cellular derivatives are required by these pathways. Thus most efforts have been focused on design of small molecules with similar structures to folates as antitumor drugs (i.e. anti-folate). However, as folates are involved in many cellular processes, folate-based drugs might interfere with other metabolic pathways, which would result in adverse side effects, such as general cytotoxicity. Ten enzymatic reactions in de novo purine biosynthesis pathway are coupled together to produce the final product, purine nucleotides. Of these enzymes, ATIC is a bifunctional enzymes that catalyze the last two enzymatic reactions. The major goal of this project is to design novel inhibitors of ATIC via structure-based drug design. These novel inhibitors will be specifically tailored to bind ATIC, inhibiting its enzymatic activity, which in turn will block the de novo purine biosynthesis pathway. This approach represents an attractive strategy to develop antitumor drugs more efficacious and with less side effects for the treatment of various cancers, including breast cancer. In order to design these new class inhibitors, 3D structure databases will be used to screen potential lead compounds that will bind to ATIC. Enzymatic inhibition assay will evaluate how potent these compounds are in inhibiting the activity of ATIC. Three-dimensional structure of these inhibitors complexed with ATIC will provide an essential structural framework for further optimization and improvement of the inhibitors. Iterative cycles of design, evaluation, modification, and structure analysis will be performed in order to fulfill the ultimate goal of identifying clinical useful inhibitors for new treatments of breast cancer.