Amidated peptides have been shown to be autocrine/paracnne growth factors that stimulate the proliferation of a number of cancers including cancer of the lung, pancreas, stomach, brain, endometrium, ovary, and prostate. Neutralization of the growth stimulatory a-amidated peptide hormones using either specific peptide analogs or antibodies targeted against a specific peptide has been a successful treatment for cancer. The best-known example is the use of analogs of luteinizing hormone-releasing hormone (LH-RH) for the treatment of advanced androgen-dependent prostatic cancer. In 70 percent of cases, primary treatment consists of the administration of a LH-RH analog. A number of different a-amidated peptides have been implicated in cancer proliferation and some cancers produce an array of growth stimulatory amidated peptides. Thus, a strategy predicted on one drug specifically targeted to neutralize one a-amidated peptide will never be a general treatment for cancer. A better strategy would be to develop a single drug that would inhibit the production of all growth stimulatory a-amidated peptide hormones. Such an approach is feasible because only one pathway is responsible for the production of all a-amidated peptide hormones. One of the enzymes in the a-amidated peptide hormone biosynthetic pathway is peptidyiglycine a-amidating monooxygenase (PAM). PAM catalyzes the oxidative cleavage of C-terminal glycine-extended prohormones to the alpha-amidated peptide and glyoxylate. We have recently discovered that S- [phenyl(thioacyl)]thioglycolates (Ar-(CH2)n-CS-S-CH2-COOH) inhibit PAM with inhibition constants in the low micromolar range. The broad goal of this project is to develop a novel S- [phenyl(thioacyl)]thioglycolic acid as potent, specific anti-PAM anti-cancer drug. In order to accomplish our goal, we specifically propose to:1. Develop an S- [phenyl(thioacyl)]thioglycolic acid that inhibits PAM with high affinity.2. Demonstrate that our optimized PAM inhibitor will halt the proliferation of cultured prostate and small-cell lung cancer cells.The successful completion of this research will validate PAM a about target for anticancer drugs and will lead to chemotherapeutics that could prove broadly useful in the treatment of cancer.
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