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: 10451076
• 负责人: Tadatoshi Sato
• 金额: --
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 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 2022-09-26
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451076
• 关键词: Address; Age; Astronauts; Binding; Biocompatible Materials; Bone Resorption; Bone Tissue; Bone necrosis; Calcium; Clinical Trials; Deterioration; Development; 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; Minerals; Modeling; Morbidity - disease rate; Mus; Musculoskeletal; Oral; Organ; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; PTK2 gene; PTK2B gene; Pain; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phosphotransferases; Predisposition; Property; Quality of life; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Site; Skeletal system; Space Flight; Tail Suspension; Testing; Therapeutic; Time; 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; kinase inhibitor; mechanical load; mechanotransduction; men; mineralization; mortality; novel; 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.

项目概要/摘要 骨质疏松症是一种全身性骨骼疾病，其特征是骨量低和微结构改变 骨组织退化，从而增加骨脆性和骨折易感性。一进 50 岁以上的三名女性和五分之一的男性预计会发生骨折，导致 生活质量、疼痛、发病率和死亡率增加的限制。但大多数都很难治疗 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，而到达骨室的药物浓度非常低。 众所周知，机械负荷是增加骨形成和骨量的关键因素。 由于重力减小和骨骼卸载，宇航员在太空飞行期间会损失骨质。最近，我们 证明抑制 FAK（粘着斑激酶）可模拟骨机械负荷的影响 细胞（Sato 等人 Nat Commun，2020）。然而，FAK 及其同源物 PYK2 在几乎所有细胞中都广泛表达。 组织和器官。因此，FAK抑制剂治疗可能会引起骨外的严重副作用。到 为了解决这个问题，我们将通过双膦酸盐（BP）结合开发骨靶向FAK抑制剂。 这一高风险、高回报的提议为肌肉骨骼研究带来了相当大的潜在利益 场地。 (1) 通过 BP 结合进行骨靶向将消除 FAK 抑制剂的骨骼外副作用。 (2) 双膦酸盐可引起副作用，例如颌骨坏死和细胞毒性。然而，我们的 新型无药理学活性的 BP 解决了这一潜在问题。 (3) BP-共轭物可能会增加 FAK 抑制剂的骨形成功效比原来高约 10 至 1000 倍，因为 缀合方法递送至靶位点并在高浓度下选择性地释放活性药物（FAK 抑制剂） 骨代谢部位。 (4) BP-FAK抑制剂不会导致血清钙升高，尽管目前 骨形成诱导药物，如特立帕肽 (PTH1-34) 和 abaloparatide（PTH 类似物）。 (5)FAK抑制剂 正在进行某些癌症疗法的多项临床试验。因此，双膦酸盐结合的 FAK 抑制剂是 临床相关药物作为骨特异性骨形成诱导剂。 (6) 这种 BP 共轭可以减少 由于双膦酸盐生物材料特性与羟基磷灰石结合并保留而导致的给药频率 在网站上。 (7) 我们可能会采取新的制剂策略来解决口服可用性的限制。 该提案的目标 1 将开发和评估 BP 结合的骨靶向 FAK 抑制剂 (VS-6063) 体外（成骨细胞、破骨细胞和骨细胞）。在目标 2 中，我们将执行后肢卸载动物模型： 不再使用骨质疏松症来定义 FAK 抑制剂对骨的治疗作用。这将提供数以千计的新 用于最终开发可成药 BP-FAK 抑制剂缀合物的候选 FAK 底物。采取 这些研究将共同​​开发新型骨靶向药物来模拟机械转导 并治疗固定引起的骨质流失。