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.

项目摘要/摘要 骨质疏松症是一种以低骨量和微结构为特征的全身性骨骼疾病 骨组织退化，随之而来的是骨脆性和骨折易感性的增加。一合一 据预测，50岁以上的女性中有3人，男性中每5人中就有一人患有骨折，导致癌症 生活质量的局限性、疼痛、发病率和增加的死亡率。然而，它是最难治疗的 非骨选择性给药的骨骼系统疾病。内脏器官可能暴露在 大量的药物，而极低的药物浓度到达骨间室。 众所周知，机械负荷是增加骨形成和骨量的关键因素。 宇航员在太空飞行过程中由于重力降低和骨骼卸载而失去骨量。最近，我们 证实抑制粘着斑激酶(FAK)可以模拟骨中机械负荷的影响 Cells(Sato et al.NAT Commun，2020)。然而，FAK及其同源物PYK2在几乎所有的 组织和器官。因此，FAK抑制剂治疗可能会引起严重的骨外副作用。至 为了解决这个问题，我们将通过双膦酸盐(BP)的结合来开发骨靶向FAK抑制剂。 这项高风险、高回报的建议为肌肉骨骼研究带来了相当大的潜在好处。 菲尔德。(1)通过BP偶联的骨靶向治疗可以消除FAK抑制剂的骨外副作用。(2) 双膦酸盐可能会引起副作用，如颌骨坏死和细胞毒性。然而，我们的 新的药物非活性BP解决了这一潜在的问题。(3)BP-偶联物可能增加 FAK抑制剂的效果比原来的高出约10到1000倍，因为 偶联法高选择性地将活性药物(FAK抑制剂)释放到靶部位 骨骼代谢部位。(4)BP-FAK抑制剂不能使血清钙升高，尽管目前 骨形成诱导性药物，如Teriparatide(PTH1-34)和abaloparatide(PTH类似物)。(5)FAK抑制剂 正在对某些癌症疗法进行几项临床试验。所以，双膦酸偶联的FAK抑制剂是 临床相关药物如骨特异性骨形成诱导剂。(6)这种BP-共轭可以减少 双膦酸类生物材料与羟基磷灰石结合并滞留的给药频率 在网站上。(7)我们的新配方策略可能会被用来解决口服利用度的限制。 本方案的目标1将开发和评价BP偶联骨靶向FAK抑制剂(VS-6063)。 体外培养(成骨细胞、破骨细胞和骨细胞)。在目标2中，我们将进行后肢卸载动物模型 停用骨质疏松症来确定FAK抑制剂在骨骼中的治疗作用。这将提供数千个新的 用于最终开发可药物BP-FAK抑制剂共轭化合物的候选FAK底物。已被占用 总之，这些研究将开发新的骨靶向药物来模拟机械转导。 并治疗制动引起的骨丢失。