Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery
Allosteric non-bisphosphonate FPPS inhibitors identified by fragment-based discovery
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DOI：
10.1038/nchembio.421
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发表时间：
2010-09-01
影响因子：
14.8
通讯作者：
Green, Jonathan R.
中科院分区：
文献类型：
--
作者：
Jahnke, Wolfgang;Rondeau, Jean-Michel;Green, Jonathan R.
二膦酸盐是法呢基焦磷酸合酶（FPPS）的有效抑制剂，并且在治疗骨疾病如骨质疏松症、佩吉特病和肿瘤诱导的骨质溶解中非常有效。此外，在体外和体内研究的基础上已经假定了直接抗肿瘤作用的潜力，最近在使用强效双膦酸盐唑来膦酸治疗的早期乳腺癌患者中得到了临床证明。然而，双膦酸盐对骨矿物质的高亲和力似乎不适合直接治疗软组织肿瘤。在这里，我们报告了第一个有效的非双膦酸盐FPPS抑制剂的发现。这些新的抑制剂与FPPS上一个以前未知的变构位点结合，该位点是通过使用NMR和X射线晶体学的基于片段的方法鉴定的。这种变构和可药物化的口袋允许开发新一代FPPS抑制剂，其针对软组织中的直接抗肿瘤作用进行了优化。
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.