Inhibiting Fornesyl Protein Transferase with Sch-66336: Potentially a Selective, Noncytotoxic Therapy for Human Cancer

摘要

The discovery of Farnesyl Protein Transferase (FPT) and its role in signal transduction and cellular proliferation has inspired the identification of inhibitors of this process as potential cancer therapy. Although thousands of FPT inhibitors (FTIs) have been prepared, only a select few have advanced to human clinical trials. Sch-66336, a potent FTI with demonstrated in vivo efficacy in mice, is currently in Phase II clinical trials for the treatment of human cancers. Structure Activity Relationship studies, which led to the discovery of Sch-66336, are described and related to the observed differences in interactions made with FPT as determined by x-ray crystal structure analysis. Its potency against a panel of tumor cell lines and its efficacy in mouse models as mono or combination therapy is reviewed.