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。除了人类遭受的巨大痛苦外，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。它的抑制已被证明有效地降低了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，这些化合物的主要来源是某些传统上用于骨骼疾病的中草药。最近，我们在骨质疏松症模型中展示了其中一种化合物的有效性，没有任何可观察到的副作用。该项目将扩展这种方法，并将从草药化合物中产生更多有效和可药物的衍生品。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 sideeffect of the most common breast and prostate cancer. Aside from human suffering enormousfinancial health care costs are added to the treatment of these diseases. Current treatmentshave various shortcomings and side effects, which include increased cancer risks, atypicalfractures, bone necrosis, infections, and vascular problems. There is clearly a need for moreeffective and safer treatments. Unfortunately, little progress has been made in recent years.Most treatments attack rather non-specifically entire cells or block complex pathways, whichis likely causing the side effects. In contrast, the protease, cathepsin K, is solely responsiblefor the bone degradation and significantly contributes to joint erosion. Its inhibition has beenshown to effectively reduce fracture rates in post-menopausal women. However, thistreatment also had severe side effects leading to the termination of the further development ofcathepsin K inhibitors. Our research has identified and verified a novel type of cathepsin Kinhibitors without causing any of the side effects seen in clinical trials. Interestingly, a majorsource 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 modelwithout any observable side effects. This project will expand this approach and will generatemore potent and druggable derivatives from the herbal compounds. Compounds will beanalyzed in arthritis and bone cancer mouse models. We anticipate that these compounds willhave a superior efficacy with no or fewer side effects than current treatment regimes. Thisproject requires a strong interdisciplinary collaboration between chemists, pharmaceuticalscientists, biochemists, and animal model researchers and will provide an excellentopportunity for the training of students.