Developing and evaluating bone targeting agents to mimic the skeletal effects of mechanical loading

开发和评估骨靶向剂以模拟机械负荷的骨骼效应

• 批准号: 10709497
• 负责人: Tadatoshi Sato
• 金额: $ 28.91万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10709497
• 关键词: Address; Age; Astronauts; Binding; Biocompatible Materials; Bone Resorption; Bone Tissue; Bone necrosis; Calcium; Clinical Trials; Deterioration; Development; Disease; Dose; Drug Delivery Systems; Exposure to; Focal Adhesion Kinase 1; Formulation; Forteo; Fracture; Frequencies; Health; Hindlimb Suspension; Homologous Gene; Hydroxyapatites; Hypogravity; Immobilization; In Vitro; Injections; Jaw; Metabolic; Methods; Modeling; Morbidity - disease rate; Mus; Musculoskeletal; Oral; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; PTK2B gene; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phosphotransferases; Predisposition; Property; Quality of life; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Site; Space Flight; System; Tail Suspension; Testing; Therapeutic; Tissues; Validation; Visceral; Woman; Work; analog; bisphosphonate; bone; bone cell; bone disuse atrophy; bone fragility; bone loss; bone mass; cancer therapy; clinically relevant; cytotoxicity; high reward; high risk; improved; inhibitor; kinase inhibitor; mechanical load; mechanotransduction; men; mineralization; mortality; novel; pharmacologic; side effect; skeletal; skeletal disorder; skeletal unloading; systemic toxicity; targeted agent; tool

Project Summary/ Abstract Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. One in three women and one in five men over the age of 50 years are predicted to suffer a fracture leading to limitations in the quality of life, pain, morbidity, and increased mortality. However, it is difficult to treat most diseases of the skeletal system with non-bone selective drug delivery. Visceral organs may be exposed to the bulk of the pharmaceutical drug, while very low drug concentrations reach the bone compartment. Mechanical loading is well known as a key factor that can increase bone formation and bone mass. Astronauts lose bone mass during space flight due to reduced gravity and skeletal unloading. Recently, we demonstrated that inhibiting FAK (Focal adhesion kinase) mimics the effects of mechanical loading in bone cells (Sato et al. Nat Commun, 2020). However, FAK and its homolog, PYK2 are widely expressed in almost all tissues and organs. Therefore, FAK inhibitor treatment may cause severe side-effects outside of bone. To address this problem, we will develop bone-targeted FAK inhibitors via bisphosphonate (BP) conjugation. This high-risk, high-reward proposal brings considerable potential benefit to the musculoskeletal research field. (1) Bone targeting via BP-conjugation will eliminate extra-skeletal side effects of FAK inhibitors. (2) Bisphosphonates can cause side effects such as osteonecrosis of the jaw and cytotoxicities. However, our novel pharmacologically-inactive BP addresses this potential concern. (3) The BP-conjugates may increase FAK inhibitors' efficacy to around 10 to 1000 times higher bone formation than the original because this conjugation method delivers to the target sites and releases the active drug (FAK inhibitor) selectively at high bone metabolic sites. (4) There can be no serum calcium elevation by BP-FAK inhibitors, although current bone formation inducible drugs like teriparatide (PTH1-34) and abaloparatide (PTH analog). (5) FAK inhibitors are under several clinical trials for certain cancer therapies. So, bisphosphonate-conjugated FAK inhibitors are clinically relevant drugs as bone-specific bone formation induced agents. (6) This BP-conjugation can reduce administration frequencies due to bisphosphonate biomaterial property that binds to hydroxyapatite and stays on the sites. (7) Our new formulation strategies may be pursued to address oral availability limitations. Aim 1 of this proposal will develop and evaluate BP-conjugated bone-targeting FAK inhibitor (VS-6063) in vitro (osteoblasts, osteoclasts, and osteocytes). In aim 2, we will perform hindlimb unloading animlal model as disuse osteoporosis to define the therapeutic action of FAK inhibitors in bone. This will offer thousands of new candidate FAK substrates for the final development of a druggable BP-FAK inhibitor conjugate. Taken together, these studies will develop novel bone-targeted pharmacologic agents to mimic mechanotransduction and treat immobilization-induced bone loss.

项目摘要/摘要 骨质疏松症是一种全身性骨骼疾病，其特征是低骨量和微构造性的特征 骨组织恶化，导致骨骼脆弱性和骨折易感性增加。一个英寸 预计有三名女性和50岁以上的五分之一的男性会遭受骨折 生活质量，疼痛，发病率和死亡率增加的限制。但是，很难治疗 具有非骨选择性药物输送的骨骼系统疾病。内脏器官可能会暴露于 大部分药物，而药物浓度非常低，到达骨室。 机械负荷是可以增加骨形成和骨骼质量的关键因素。 由于重力减少和骨骼卸载，宇航员在太空飞行过程中失去了骨骼质量。最近，我们 证明抑制FAK（局灶性粘附激酶）模仿了骨骼机械负荷的影响 细胞（Sato等人Nat Commun，2020年）。但是，FAK及其同源物Pyk2几乎在所有人中广泛表达 组织和器官。因此，FAK抑制剂治疗可能会在骨外引起严重的副作用。到 解决了这个问题，我们将通过双膦酸盐（BP）结合开发针对骨的FAK抑制剂。 这个高风险的高回报提案为肌肉骨骼研究带来了可观的潜在益处 场地。 （1）通过BP结合的骨头靶向将消除FAK抑制剂的骨骼外副作用。 （2） 双膦酸盐会引起副作用，例如颌骨的骨坏死和细胞毒性。但是，我们的 新颖的药理学不活跃的BP解决了这一潜在问题。 （3）BP结合物可能会增加 FAK抑制剂的功效比原来的骨形成率高约10至1000倍 共轭方法可将目标部位传递并在高中释放活性药物（FAK抑制剂） 骨代谢部位。 （4）尽管电流 骨形成诱导药，如teriparatide（PTH1-34）和鲍帕吡啶胺（PTH类似物）。 （5）FAK抑制剂 正在接受一些癌症疗法的临床试验。因此，双膦酸盐偶联的FAK抑制剂是 临床相关的药物作为骨特异性骨形成诱导的药物。 （6）这种BP结合可以减少 与羟基磷灰石结合的双膦酸盐生物材料特性引起的给药频率 在网站上。 （7）我们的新配方策略可能会被采用以解决口腔可用性限制。 该提案的目标1将开发和评估BP偶联的骨靶向FAK抑制剂（VS-6063） 体外（成骨细胞，破骨细胞和骨细胞）。在AIM 2中，我们将执行后肢卸载动画模型作为 废除骨质疏松症来定义FAK抑制剂在骨骼中的治疗作用。这将提供数千个新的 候选FAK底物，用于最终开发可毒bp-fak抑制剂结合物。拍摄 总之，这些研究将开发出新颖的骨针对性药理学剂，以模拟机械转导的剂量。 并治疗固定化引起的骨质流失。