Side effect-free cathepsin K targeting drugs for skeletal diseases

用于骨骼疾病的无副作用组织蛋白酶 K 靶向药物

• 批准号: 523434-2018
• 负责人: Bromme, Dieter
• 金额: $ 8.88万
• 依托单位: University of British Columbia
• 依托单位国家: 加拿大
• 项目类别: Collaborative Health Research Projects
• 财政年份: 2018
• 资助国家: 加拿大
• 起止时间: 2018-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=646309
• 关键词: Side; effect; free; cathepsin; targeting

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.

关节炎疾病影响15%的人口，骨癌是最常见的乳腺癌和前列腺癌的常见转移性副作用。除了人类的痛苦之外，治疗这些疾病还增加了巨大的医疗保健费用。目前的治疗方法有各种缺点和副作用，包括增加癌症风险，非典型骨折，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。不幸的是，近年来进展甚微。大多数治疗攻击非特异性的整个细胞或阻断复杂的途径，这可能导致副作用。相比之下，蛋白酶，组织蛋白酶K，是唯一负责 ** 骨降解和显着有助于关节侵蚀。它的抑制作用已被证明能有效降低绝经后妇女的骨折率。然而，这种 ** 治疗也有严重的副作用，导致 ** 组织蛋白酶K抑制剂的进一步发展终止。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观察到的任何副作用。有趣的是，这些化合物的主要来源是传统上用于骨骼疾病的某些中草药。最近，我们已经在骨质疏松症模型 ** 中显示了这些化合物之一的功效，而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有效和更可药用的衍生物。将在关节炎和骨癌小鼠模型中分析化合物。我们预期这些化合物将 ** 具有上级功效，并且没有或比当前治疗方案更少的副作用。这个项目需要化学家、制药科学家、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。