Novel inhibitors of carboxypeptidase G(2) (CPG(2)): Potential use in antibody-directed enzyme prodrug therapy

The design and synthesis of potent thiocarbamate inhibitors for carboxypept idase Ga are described. The best thiocarbamate inhibitor N-(p-methoxybenzen ethiocarbonyl)amino-L-glutamic acid 6d, chosen for preliminary investigatio ns of in vitro antibody-directed enzyme prodrug therapy (ADEPT), abrogated the cytotoxicity of a combination of A5B7-carboxypeptidase G(2) conjugate a nd prodrug PGP (N-p-{N,N-bis (2-chloroethyl)amino}phenoxycarbonyl-L-glutama te) toward LS174T cells. This is the first report of a small-molecule enzym e inhibitor proposed for use in conjunction with the ADEPT approach.