Bisphosphonates targeting geranylgeranyl diphosphate synthase: A QSAR investigation

MEDI 113

Rong Cao, rongcao@chad.scs.uiuc.edu1, Yonghui Zhang, yhzhang@chad.scs.uiuc.edu2, Fenglin Yin, fyin@uiuc.edu3, Michael P. Hudock, hudock@uiuc.edu1, and Eric Oldfield, eo@chad.scs.uiuc.edu2. (1) Center for biophysics and computational biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, (2) Department of Chemistry, University of Illinois at Urbana-Champaign, 600S. Mathews Avenue, Urbana, IL 61801, (3) Center for Biophysics and Computational Biology, University of Illinois at Urbana Champaign, 600 S. Mathews Avenue, Urbana, IL 61801
Protein prenylation, including farnesylation and geranylgeranylation, is an important posttranslational modification that either anchors proteins to membranes or facilitates protein-protein binding. Blocking protein prenylation has been shown to represent a potentially useful therapeutic approach for cancer therapy. We thus synthesized and tested a series of bisphosphonates targeting human geranylgeranyl diphosphate synthase (GGPPS). The most active compound has an IC50 of 300 nM against the enzyme and possesses low micro-molar activity against tumor cell lines. A QSAR analysis of GGPPS inhibitors indicates the importance of hydrophobic and steric interactions but not positive charge character required in farnesyl diphosphate synthase (FPPS) inhibition. The results suggest a different inhibitor binding mode in GGPPS.
 

Poster Session
7:00 PM-9:00 PM, Sunday, August 19, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

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