Inhibitors of the FBP-FUSE interaction as potential anticancer agents

MEDI 16

Pauline N. Wyrembak1, Matthew P. Glenn1, Demetrios T. Braddock2, and Andrew D. Hamilton, andrew.hamilton@yale.edu1. (1) Department of Chemistry, Yale University, 225 Prospect St, New Haven, CT 06520-8107, (2) Department of Pathology, Yale University School of Medicine, 310 Cedar St, New Haven, CT 06510
Deregulated or elevated expression of c-myc has been implicated in a wide array of human carcinomas making it an attractive target for molecular chemotherapy. Several experiments have shown that disruption of far-upstream element (FUSE) binding protein (FBP) function may lead to the inhibition of c-myc driven tumors. FBP regulates c-myc expression through its interaction with single-stranded FUSE located upstream of the c-myc promoter. Here, we report the design and synthesis of compounds that target the FBP-FUSE protein-DNA interaction. Initial inhibitors based on a lead ligand display micromolar affinity in vitro and predominantly target the DNA binding domain of FBP as determined by HSQC NMR experiments. Alternative approaches to disrupt this interaction were also explored. Inhibitors identified through multiple strategies will be further optimized towards increasing potency and specificity to provide a set of molecular probes that will be used to validate FBP as a target for anti-cancer therapy.
 

Medicinal Chemistry Award Symposium
1:30 PM-4:20 PM, Sunday, August 19, 2007 BCEC -- 210B, Oral

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007