Development of NNMT inhibitors as novel interventions to activate quiescent muscle stem cells and improve age-related muscle degeneration

开发 NNMT 抑制剂作为激活静止肌肉干细胞并改善与年龄相关的肌肉退化的新型干预措施

• 批准号: 9905476
• 负责人: Stanley J Watowich
• 金额: $ 19.75万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905476
• 关键词: Acute; Address; Adult; Adverse effects; Adverse event; Age; Age-Years; Aging; American; Animals; Area; Atrophic; Attenuated; Biological Assay; Biological Availability; Blinded; Body Weight; Cardiovascular system; Cell Aging; Cellular Metabolic Process; Chemistry; Chronic; Chronic Disease; Clinical; Cytochrome P450; Defect; Development; Diagnostic; Diet; Disease; Dose; Drug Interactions; Drug Kinetics; Eating; Elderly; Enzymes; Epigenetic Process; Etiology; Family; Fatigue; Functional disorder; Gender; Growth; Half-Life; Health; Health Personnel; Healthcare; Hematology; Histopathology; Homeostasis; Human; In Vitro; Individual; Industry; Injury; Intervention; Lead; Lesion; Longevity; Maximum Tolerated Dose; Mediating; Modeling; Monitor; Morbidity - disease rate; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle Mitochondria; Muscle function; Muscle satellite cell; Nicotinamide N-Methyltransferase; Oral; Organ Weight; Parents; Pathway interactions; Permeability; Pharmaceutical Preparations; Pharmacology; Physical activity; Physiological; Population; Program Development; Property; Proteins; Quality of life; Research; Risk; Rodent Model; S-Phase Fraction; SIRT1 gene; Safety; Series; Serum; Skeletal Muscle; Solubility; Syndrome; Technology; Testing; Therapeutic; Time; Toxic effect; Treatment Efficacy; United States National Institutes of Health; age related; age-related muscle loss; aged; base; care providers; cell age; cohort; comorbidity; comparative; cost effective; design; disability; drug candidate; drug development; drug metabolism; evidence base; exercise training; experience; frailty; functional improvement; genotoxicity; high reward; improved; in vivo; in vivo Model; inhibitor/antagonist; lead series; lifestyle intervention; medication safety; metabolic profile; mortality; mouse model; muscle aging; muscle degeneration; muscle form; muscle hypertrophy; muscle regeneration; muscle strength; novel; novel therapeutics; preclinical study; predictive modeling; premature; prevent; reduce symptoms; reduced muscle strength; regenerative; repaired; resistance exercise; respiratory; safety assessment; safety study; sarcopenia; skeletal muscle wasting; small molecule; treatment strategy

ABSTRACT For largely unknown reasons, aging is accompanied by progressive loss of skeletal muscle mass, strength, function, and regenerative capacity.1 By the time US adults reach 60 years of age, 30% will suffer from sarco- penia, characterized by clinically recognizable chronic muscle degeneration manifesting as extreme fatigue, weakness, and greatly reduced physical activity.3-5 This condition typically progresses to highly debilitating frailty syndrome. Treating this age-associated chronic disease is critical to avoid significant decreases in the quality of life among older adults. An estimated 15M US adults suffer with sarcopenia, and this chronic disease will become increasingly pervasive and an ever greater healthcare problem as the number of older Americans steadily increase over the next 30 years. Given the scope and impact of this chronic disease, there is a clear unmet need for drugs that slow, stop, or reverse sarcopenia and thus significantly improve the quality of life for aging Americans with deteriorating muscle function. Although the etiology of sarcopenia is not well understood, current research suggests that a critical deter- minant of sarcopenia is muscle stem cell (muSC) senescence. A working mechanism for the development of muSC senescence is as follows: as muscle cells age, they progressively develop increased expression and/or activity of nicotinamide N-methyltransferase (NNMT), which results in lowered intracellular NAD+ levels, re- duced SIRT1 activity, increased premature differentiation of muSCs, and elevated muSC senescence that ul- timately interferes with muSC-mediated muscle growth and homeostasis. Recently, we developed small molecules that selectively inhibit NNMT, activate the NAD salvage pathway, and increase intracellular levels of NAD+. Our lead series of NNMT inhibitors have excellent physicochemical properties (e.g., high solubility, stability, permeability), high selectivity, clean off-target pharmacological profile, promising pharmacokinetic profile (e.g., high oral bioavailability, 20-hr half-life), and no apparent signs of early toxicity/adverse indications. Our preliminary in vivo studies have demonstrated that NNMT inhibitors can increase muSC activity and re- generative capacity, enhance muscle fiber growth, and improve muscle mitochondrial respiratory capacity and function in aged mice. Based on these promising results we hypothesize that small molecule NNMT inhibi- tors can safely normalize defects in aged muscle pathophysiology and mitigate/reverse sarcopenia. This hypothesis will be tested using translationally-relevant in vivo models for muscle regeneration, repair, and function and in vitro and in vivo models for drug safety. Upon successful completion of this project, a drug can- didate will be identified that could advance to IND-directed preclinical studies. The assembled project team has extensive expertise ranging from drug development to in vivo muscle function assessment, and is eminently qualified to perform the described studies and successfully complete this project.

摘要 由于很大程度上未知的原因，衰老伴随着骨骼肌质量、力量、 功能和再生能力。1到美国成年人达到60岁时，30%的人将患有肉瘤， 肌肉萎缩症，其特征在于临床上可识别的慢性肌肉退化，表现为极度疲劳， 虚弱，身体活动大大减少。3 -5这种情况通常进展到高度衰弱 虚弱综合征治疗这种与年龄相关的慢性疾病是至关重要的，以避免显着减少， 老年人的生活质量。估计有1500万美国成年人患有肌肉减少症，这种慢性疾病 随着美国老年人的数量增加， 在未来30年内稳步增长。鉴于这一慢性疾病的范围和影响， 对减缓、停止或逆转肌肉减少症的药物的未满足的需求，从而显著改善肌肉减少症的质量。 肌肉功能恶化的美国老年人的生活。 虽然肌肉减少症的病因还没有很好地理解，目前的研究表明，一个关键的阻止- 肌肉减少症的主要原因是肌肉干细胞（muSC）衰老。发展的工作机制 muSC衰老如下：随着肌肉细胞老化，它们逐渐发展增加的表达和/或 烟酰胺N-甲基转移酶（NNMT）的活性，导致细胞内NAD+水平降低， 诱导SIRT 1活性，增加muSC的过早分化，并增加muSC衰老， 最终干扰muSC介导的肌肉生长和稳态。最近，我们开发了小型 选择性抑制NNMT、激活NAD补救途径并增加细胞内 NAD+。我们领先的NNMT抑制剂系列具有优异的理化性质（例如，溶解度高， 稳定性、渗透性）、高选择性、干净脱靶药理学特征、有前景的药代动力学 简档（例如，高口服生物利用度，20小时半衰期），并且没有明显的早期毒性/不良适应症迹象。 我们的初步体内研究表明，NNMT抑制剂可以增加muSC活性，并重新激活muSC。 生殖能力，增强肌纤维生长，提高肌肉线粒体呼吸能力， 老年小鼠的功能。基于这些有希望的结果，我们假设小分子NNMT是一种具有生物学活性的蛋白质。 Tors可以安全地使老年肌肉病理生理学缺陷正常化并减轻/逆转肌肉减少症。 这一假设将使用预防相关的肌肉再生、修复和修复的体内模型进行测试。 功能和药物安全性的体外和体内模型。在这个项目成功完成后，药物可以- 将确定可以推进IND指导的临床前研究的didate。项目组已 广泛的专业知识，从药物开发到体内肌肉功能评估， 有资格进行所述研究并成功完成该项目。