) The principal goal of the Program 1 of this NCDDG is to design, synthesize and evaluate potent inhibitors of the enzyme geranylgeranyltransferase-1 (PGGTase-I). Our recent work has shown that this enzyme plays an important role preparing the cell for key events in the pathways that control cell growth and division. As such, PGGTase-I represents a compelling target for the design of inhibitors that may find use as anti-cancer agents. Within this main thrust are the following goals: 1) To design and synthesize potent, highly selective and non-peptide inhibitors of PGGTase-I. Our approach will involve both rational, structure based methods as well as combinatorial approaches to screening different scaffold structures and functionalized derivatives. 2) To develop peptidomimetic inhibitors that do not contain a C-terminal leucine derivative. This is the critical directing element in geranylgeranylated proteins in Nature and is present in all of our early PGGTase inhibitor leads. In order to improve activity, pharmacokinetics and bioavailability it is essential that we replace the leucine residue by a less peptidic and reactive group. We will initially probe the conformational requirements of the leucine by synthesizing a series of conformationally constrained methanoleucine analogs. We will further investigate the use of a series of heterocyclic groups to replace the leucine but retain key hydrogen bonding and hydrophobic interactions to the enzyme. We will also use combinatorial methods to screen different C-terminal groups. 3) To probe the hydrophobic spacer requirements as well as the zinc binding, N-terminal regions of the inhibitors. We will place particular focus on identifying improved zinc coordinating ligands based initially on imidazole and later on other coordinating groups. A major focus will be to enhance the potency and selectivity of these agents relative to the other prenyltransferase enzymes, farnesyltransferase and geranylgeranyl-transferase-II. We will also use the extensive structure-activity profile that is generated by our synthetic designs to improve the pharmacokinetics and bioavailability of the inhibitors and to optimize their performance as in vivo anticancer agents. In addition we will synthesize bisubstrate transition state analogs of PGGTase-I as well as mechanism based inhibitors that lead to covalent modification of the enzyme.
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