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PANK Activators for the treatment of pantothenate kinase-associated neurodegeneration

PANK 激活剂用于治疗泛酸激酶相关神经变性

基本信息

批准号：
10678455
负责人：
Anasuya C Pal
金额：
$ 35.96万
依托单位：
VIRTUS THERAPEUTICS CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10678455
关键词：
Anabolism Animals Binding Biochemical Biological Biological Assay Brain Cells Cessation of life Chemicals Clinical Coenzyme A Collaborations Cytoplasm Data Defect Dementia Deposition Development Disease Disease Progression Drug Kinetics Enzymes Family Functional disorder Future Generations Genes Goals Homeostasis Human Human Activities Human Cell Line Human Genome Immobilization In Vitro Iron Kinetics Knowledge Lead Libraries Life Metabolic Metabolic Pathway Metabolism Mitochondria Mitochondrial Diseases Monitor Mus Mutate Mutation Neurodegenerative Disorders Normal Cell Organ Pantothenate kinase Pantothenate kinase-associated neurodegeneration Pantothenic Acid Patient-Focused Outcomes Patients Permeability Pharmaceutical Chemistry Phase Phenotype Phosphorylation Physiological Plasma Production Property Protein Isoforms Protein Kinase Research Safety Small Business Innovation Research Grant Solubility Testing Therapeutic Therapeutic Index Tissues Toxic effect Triazoles analog autosome candidate identification cellular imaging clinical candidate clinical development cofactor efficacy evaluation emerging adult enzyme activity high throughput screening improved in vitro activity in vivo in vivo evaluation lead candidate lead optimization mitochondrial metabolism mouse model novel novel marker rare genetic disorder repaired research clinical testing response screening small molecule small molecule libraries success symptom management treatment strategy vitamin metabolism

项目摘要

SUMMARY Pantothenate kinase-associated neurodegeneration, PKAN, is a rare progressive neurodegenerative disorder associated with iron accumulation in the brain. The disease causes early immobility and often death by early adulthood. PKAN is caused by mutations in one of four human pantothenate kinase genes, PANK2 gene, which encodes a mitochondrial pantothenate kinase. Consistent with the clinical presentation of PKAN in humans, cell biological analyses from patient-derived cells as well as phenotypic characterization of mouse models of PKAN have demonstrated that the loss of PANK2 activity results in major metabolic, cellular and physiological defects. We have recently discovered that PKAN disease has the hallmarks of a mitochondrial disorder with large accumulation of mitophagosomes. This has led us to discover a novel biomarker that could be used to differentiate between PKAN and normal cells using cell imaging. To date, no specific or established therapy exists for PKAN with most treatments directed towards managing symptoms and to slow disease progression. We hypothesize that activation of the human PANK3 (hPANK3) enzyme would result in stimulation of CoA production in PANK2 mutated cells and would represent an ideal treatment of PKAN. Chemical screening and subsequent medicinal chemistry optimization (SAR) of the lead chemotype identified 9 human PANK3 activators (VTAC1-9) that strongly activate hPANK3 with AC50 values in the nM range. These compounds do not affect the activity of human PANK1 or PANK2, show no toxicity against four human cell lines and one primary human cell, and have desirable functionality and solubility properties. Pharmacokinetics studies in mice with the early leads VTAC1 and VTAC2 demonstrated both plasma and brain exposure, excellent t½, and no apparent toxicity. Together these data indicate that these compounds are ideal candidates for the development of an effective and safe PKAN therapy. The goal of the proposed research is to conduct detailed characterization of active VTACs and a library of their analogs to identify late leads that could be advanced towards future clinical development. Towards this end, we will pursue the following three specific aims. In Aim 1, we will complete current SAR on this family compounds by characterizing the biochemical activity, selectivity and physico- chemical properties of an already synthesized 29 analogs and an additional 200 compounds to be evaluated on an iterative basis. In Aim 2, we will conduct cell-based assays to identify compounds with excellent in vitro therapeutic index and can restore biological activity in pank2-deficient cells. In Aim 3, we will conduct ADME and PK analyses and evaluate the in vivo efficacy of VTAC1 and VTAC2 and new leads from Aim 1 in pank2-/- mice by monitoring important PKAN biological metrics including activation of the CoA metabolic pathway, iron homeostasis, mitochondrial metabolism, and rescue of PKAN-like phenotypes. The success of these studies will set the stage for future clinical evaluation of a lead activator of hPANK3 as a possible effective and safe treatment for PKAN.

概括泛酸激酶相关神经退行性疾病 (PKAN) 是一种罕见的进行性神经退行性疾病与大脑中铁的积累有关。该疾病会导致早期无法活动，并常常过早死亡成年期。 PKAN 是由四种人类泛酸激酶基因之一 PANK2 基因突变引起的，该基因编码线粒体泛酸激酶。与人类 PKAN 的临床表现一致，细胞患者来源细胞的生物学分析以及 PKAN 小鼠模型的表型特征已经证明 PANK2 活性的丧失会导致主要的代谢、细胞和生理缺陷。我们最近发现 PKAN 疾病具有线粒体疾病的特征，具有大线粒体吞噬体的积累。这使我们发现了一种新的生物标志物，可用于使用细胞成像区分 PKAN 和正常细胞。迄今为止，还没有具体的或既定的治疗方法 PKAN 的大多数治疗旨在控制症状和减缓疾病进展。我们假设人类 PANK3 (hPANK3) 酶的激活会导致 CoA 的刺激 PANK2 突变细胞中的产生，将代表 PKAN 的理想治疗方法。化学筛选和随后对先导化学型进行药物化学优化 (SAR)，鉴定出 9 种人类 PANK3 激活剂 (VTAC1-9) 强烈激活 hPANK3，AC50 值在 nM 范围内。这些化合物不影响人类 PANK1 或 PANK2 的活性，对四种人类细胞系和一种原代人类细胞没有毒性，并具有理想的功能性和溶解性。早期先导药物在小鼠中的药代动力学研究 VTAC1 和 VTAC2 均表现出血浆和脑暴露、优异的 t½，且无明显毒性。这些数据共同表明这些化合物是开发有效且可靠的药物的理想候选者。安全的 PKAN 疗法。拟议研究的目标是对活性物质进行详细表征 VTAC 及其类似物库，用于识别可推进未来临床的晚期线索发展。为此，我们将努力实现以下三个具体目标。在目标 1 中，我们将完成通过表征生化活性、选择性和物理特性，目前对该家族化合物的 SAR 已合成的 29 种类似物和另外 200 种待评估化合物的化学性质迭代的基础。在目标 2 中，我们将进行基于细胞的测定，以鉴定具有优异体外实验性能的化合物治疗指数并可以恢复 pank2 缺陷细胞的生物活性。在目标 3 中，我们将进行 ADME PK 分析和评估 VTAC1 和 VTAC2 以及来自 Aim 1 的新先导在 pank2-/- 中的体内功效小鼠通过监测重要的 PKAN 生物指标，包括 CoA 代谢途径的激活、铁体内平衡、线粒体代谢和 PKAN 样表型的拯救。这些研究的成功将为 hPANK3 的先导激活剂作为一种可能有效且安全的治疗方法的未来临床评估奠定基础对于 PKAN 来说。