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.

概括泛素激酶相关的神经变性，PKAN是一种罕见的进行性神经退行性疾病与大脑中的铁积聚有关。该疾病会引起早期不动，并且经常在早期死亡成年。 PKAN是由四个人类泛素激酶基因Pank2基因之一突变引起的，该基因编码线粒体泛素激酶。与人类中PKAN的临床表现一致，细胞来自患者衍生细胞的生物分析以及PKAN小鼠模型的表型表征已经证明PANK2活性的丧失会导致主要的代谢，细胞和物理缺陷。我们最近发现，PKAN病具有线粒体疾病的标志线粒体的积累。这使我们发现了一种新颖的生物标志物，可以习惯使用细胞成像区分PKAN和正常细胞。迄今为止，没有具体或已建立的治疗 PKAN的存在，大多数治疗方法都用于治疗症状并减缓疾病的进展。我们假设人Pank3（Hpank3）酶的激活将导致COA刺激 PANK2突变细胞的产生将代表PKAN的理想治疗方法。化学筛选和铅化学型的随后的医学化学优化（SAR）确定了9个人Pank3激活剂（VTAC1-9）强烈激活HPANK3在NM范围内的AC50值。这些化合物不会影响人pank1或pank2的活性，对四种人细胞系和一个原发性细胞的毒性无毒性，并具有理想的功能和溶解性。早期铅的小鼠的药代动力学研究 VTAC1和VTAC2表现出血浆和大脑暴露，出色的T½，没有明显的毒性。这些数据一起表明，这些化合物是开发有效和的理想候选者安全的PKAN治疗。拟议研究的目的是进行主动的详细表征 VTAC及其类似物的库，以识别可以朝着未来临床发展的较晚线索发展。为此，我们将追求以下三个特定目标。在AIM 1中，我们将完成通过表征生化活性，选择性和物理学的表征，该家族中的当前SAR具有化合物已经合成的29种类似物的化学特性和另外200种可以评估的化合物迭代基础。在AIM 2中，我们将进行基于细胞的阿萨斯以鉴定具有出色体外的化合物治疗指数并可以恢复Pank2缺陷细胞中的生物学活性。在AIM 3中，我们将进行ADME PK分析并评估VTAC1和VTAC2的体内效率以及PANK2中的AIM 1的新线索小鼠通过监测重要的PKAN生物学指标，包括激活COA代谢途径，铁稳态，线粒体代谢和类似PKAN的表型的营救。这些研究的成功将为将来的HPANK3铅激活剂的未来临床评估奠定了基础，作为可能有效且安全的治疗对于PKAN。