Side effect-free cathepsin K targeting drugs for skeletal diseases

关节炎疾病影响了15%的人口，骨癌是最常见的乳腺癌和前列腺癌的常见转移副作用。除了人类的痛苦之外，这些疾病的治疗还增加了巨大的**财政保健费用。目前的治疗**有各种缺点和副作用，包括癌症风险增加、不典型骨折、骨坏死、感染和血管问题。显然，需要更有效、更安全的治疗方法。遗憾的是，近年来进展甚微。**大多数治疗方法攻击的是非特异性的整个细胞或阻断复杂的通路，这**可能是导致副作用的原因。相反，组织蛋白酶K是骨骼退化的唯一原因，也是关节侵蚀的主要原因。它的抑制作用已被证明能有效降低绝经后妇女的骨折发生率。然而，这种治疗也有严重的副作用，导致组织蛋白酶K抑制剂的进一步开发被终止。我们的研究已经确定并验证了一种新型的组织蛋白酶K**抑制剂，而不会引起临床试验中看到的任何副作用。有趣的是，这些化合物的一个主要来源是传统上用于骨骼疾病的某些中草药。**最近，我们展示了其中一种化合物在骨质疏松症模型中的疗效**没有任何可观察到的副作用。该项目将扩展这一方法，并将从草药化合物中产生**更有效和更具药用价值的衍生品。化合物将在关节炎和骨癌小鼠模型中进行分析。我们预计，这些化合物将**具有比目前的治疗方案更好的疗效，没有或更少的副作用。这个**项目需要化学家、药学**科学家、生物化学家和动物模型研究人员之间强有力的跨学科合作，并将为学生的培训提供一个极好的**机会。

Arthritic diseases affect 15 % of the population and bone cancer is a frequent metastatic side**effect of the most common breast and prostate cancer. Aside from human suffering enormous**financial health care costs are added to the treatment of these diseases. Current treatments**have various shortcomings and side effects, which include increased cancer risks, atypical**fractures, bone necrosis, infections, and vascular problems. There is clearly a need for more**effective and safer treatments. Unfortunately, little progress has been made in recent years.**Most treatments attack rather non-specifically entire cells or block complex pathways, which**is likely causing the side effects. In contrast, the protease, cathepsin K, is solely responsible**for the bone degradation and significantly contributes to joint erosion. Its inhibition has been**shown to effectively reduce fracture rates in post-menopausal women. However, this**treatment also had severe side effects leading to the termination of the further development of**cathepsin K inhibitors. Our research has identified and verified a novel type of cathepsin K**inhibitors without causing any of the side effects seen in clinical trials. Interestingly, a major**source of these compounds are certain Chinese herbs traditionally used in skeletal diseases.**Recently, we have shown the efficacy of one of these compounds in an osteoporosis model**without any observable side effects. This project will expand this approach and will generate**more potent and druggable derivatives from the herbal compounds. Compounds will be**analyzed in arthritis and bone cancer mouse models. We anticipate that these compounds will**have a superior efficacy with no or fewer side effects than current treatment regimes. This**project requires a strong interdisciplinary collaboration between chemists, pharmaceutical**scientists, biochemists, and animal model researchers and will provide an excellent**opportunity for the training of students.