Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery

• Published in: Nature chemical biology Vol. 6; no. 9; pp. 660 - 666
• Main Authors: Jahnke, Wolfgang, Rondeau, Jean-Michel, Cotesta, Simona, Marzinzik, Andreas, Pellé, Xavier, Geiser, Martin, Strauss, André, Götte, Marjo, Bitsch, Francis, Hemmig, René, Henry, Chrystèle, Lehmann, Sylvie, Glickman, J Fraser, Roddy, Thomas P, Stout, Steven J, Green, Jonathan R
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.09.2010; Nature Publishing Group
• Subjects: 631/154; 631/154/436/2388; 631/92/607/1172; Allosteric Regulation; Allosteric Site; Binding sites; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Bisphosphonates; Bone and Bones - chemistry; Bone and Bones - metabolism; Bone diseases; Cell Biology; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Chemotherapy; Crystallography; Crystallography, X-Ray; Diphosphonates - analysis; Diphosphonates - chemistry; Diphosphonates - metabolism; Diphosphonates - pharmacology; Drug Evaluation, Preclinical; Enzyme Inhibitors - analysis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Geranyltranstransferase - antagonists & inhibitors; Geranyltranstransferase - metabolism; Humans; Imidazoles - analysis; Imidazoles - chemistry; Imidazoles - pharmacology; Inhibitor drugs; Inhibitors; Magnetic Resonance Spectroscopy; Osteoporosis; Soft Tissue Neoplasms - drug therapy; Tumors
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.421

Although FPPS is a potential anti-cancer target, the high bone affinity of nitrogen-containing bisphosphonates, FPPS inhibitors used clinically to treat bone disease, has prevented their development as cancer therapeutics. Using fragment-based drug discovery, non-bisphosphonate inhibitors were discovered that bind in a previously undescribed allosteric pocket. Bisphosphonates are potent inhibitors of farnesyl pyrophosphate synthase (FPPS) and are highly efficacious in the treatment of bone diseases such as osteoporosis, Paget's disease and tumor-induced osteolysis. In addition, the potential for direct antitumor effects has been postulated on the basis of in vitro and in vivo studies and has recently been demonstrated clinically in early breast cancer patients treated with the potent bisphosphonate zoledronic acid. However, the high affinity of bisphosphonates for bone mineral seems suboptimal for the direct treatment of soft-tissue tumors. Here we report the discovery of the first potent non-bisphosphonate FPPS inhibitors. These new inhibitors bind to a previously unknown allosteric site on FPPS, which was identified by fragment-based approaches using NMR and X-ray crystallography. This allosteric and druggable pocket allows the development of a new generation of FPPS inhibitors that are optimized for direct antitumor effects in soft tissue.