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Allosteric non-bisphosphonate inhibitors of farnesyl pyrophosphate synthase identified by fragment-based discovery

Jahnke, Wolfgang and Rondeau, Jean-Michel and Cotesta, Simona and Marzinzik, Andreas and Pelle, Xavier and Geiser, Martin and Strauss, Andre and Goette, Marjo and Bitsch, Francis and Hemmig, Rene and Henry, Christelle and Lehmann, Sylvie and Glickman, Fraser and Roddy, Thomas and Stout, Steven and Green, Jonathan (2010) Allosteric non-bisphosphonate inhibitors of farnesyl pyrophosphate synthase identified by fragment-based discovery. Nature Chemical Biology, 6 (6). pp. 660-666. ISSN 1552-4450

Abstract

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 anti-tumor effects has been postulated based on 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. All these novel 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 anti-tumor effects in soft tissue.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2500

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