Src inhibitors in metastatic bone disease
Src inhibitors in metastatic bone disease
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DOI：
10.1158/1078-0432.ccr-06-0991
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发表时间：
2006-10-15
影响因子：
11.5
通讯作者：
Sawyer, Tomi K.
中科院分区：
文献类型：
--
作者：
Boyce, Brendan F.;Xing, Lianping;Sawyer, Tomi K.
类似于15年前，Src酪氨酸激酶在小鼠中的表达被敲除后，利用重组DNA技术，Src酪氨酸激酶是第一个被证明在骨中具有重要功能的基因产物。从那时起，我们对骨钙素调控的理解有了显着的进步，并确定了其他关键酶，这些酶在小鼠中敲除或在人类中识别出突变后调节破骨细胞的形成，活化和存活。这导致发现或开发了这些关键酶中的一些的特异性抑制剂，包括Src，作为概念验证的先导化合物或潜在的临床候选物，用于预防与骨吸收增加相关的疾病，如骨质疏松症和转移性骨疾病。虽然双膦酸盐已被证明具有预防骨质流失的改善功效，但>30年，副作用，如上消化道症状，以及要求在食物前至少2小时服用，限制了患者的依从性。因此，随着对调节破骨细胞功能的途径的了解越来越多，以及对其中一些在肿瘤细胞中也具有活性的认识，制药公司已经努力鉴定小分子先导化合物，以开发成新的治疗剂，用于预防骨丢失，其功效与双膦酸盐的功效相匹配。在这篇文章中，我们回顾了我们目前对调节破骨细胞形成、激活和存活的信号通路的理解，特别提到了Src酪氨酸激酶和下游信号的作用，并强调了在各种骨吸收增加的模型中，Src激酶抑制剂的作用，这些抑制剂已经靶向骨，以限制对其他细胞的潜在不良影响。
Src tyrosine kinase was the first gene product shown to have an essential function in bone using recombinant DNA technology after its expression was knocked out in mice similar to 15 years ago. Since then,, our understanding of the regulation of bone catabolism has advanced significantly with the identification of other key enzymes that regulate osteoclast formation, activation, and survival after their knockout in mice or recognition of mutations in them in humans. This led to the discovery or development of specific inhibitors of some of these key enzymes, including Src, as proof-of-concept lead compounds or potential clinical candidates for the prevention of diseases associated with increased bone resorption, such as osteoporosis and metastatic bone disease. Although bisphosphonates have been prescribed with proven and improving efficacy for the prevention of bone loss for >30 years, adverse effects, such as upper gastrointestinal tract symptoms, and the requirement to take them at least 2 hours before food have limited patient compliance. Thus, with growing knowledge of the pathways regulating osteoclast function and the appreciation that some of these are active also in tumor cells, drug companies have made efforts to identify small-molecular lead compounds for development into new therapeutic agents for the prevention of bone loss with efficacy that matches for supersedes that of bisphosphonates. In this article, we review our current understanding of the signaling pathways that regulate osteoclast formation, activation and survival with specific reference to the role of Src tyrosine kinase and downstream signaling and highlight in a variety of models of increased bone resorption the effects of Src kinase inhibitors that have been targeted to bone to limit potential adverse effects on other cells.