New anti-glioblastoma metabolic compounds with high potential for Blood Brain Barrier penetration

新型抗胶质母细胞瘤代谢化合物具有穿透血脑屏障的巨大潜力

基本信息

批准号：
10543931
负责人：
Krzysztof Reiss
金额：
$ 22.5万
依托单位：
WAYPATH PHARMA LLC
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-02 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10543931
关键词：
3-Dimensional Acetamides Adoptive Cell Transfers Agonist Algorithms Animal Model Animals Antineoplastic Agents Biological Availability Blood Blood - brain barrier anatomy Brain Neoplasms Caloric Restriction Cancer Vaccines Canis familiaris Cell Death Cells Central Nervous System Neoplasms Characteristics Chemical Structure Chemicals Clinical Trials Coculture Techniques Complex Computer Models Development Drug Kinetics Electron Transport Esters Evaluation Excision Exposure to Family Fenofibrate Glioblastoma Glioma Glucose Human Immune checkpoint inhibitor Immunotherapy Impotence In Vitro Intracranial Neoplasms Lipids MT3 gene Maintenance Maximum Tolerated Dose Metabolic Mitochondria Modeling Modification Molecular Molecular Structure Mus Neuraxis Operative Surgical Procedures Oral Outcome Pathway interactions Patients Pharmaceutical Preparations Phase Preparation Process Prodrugs Radiation therapy Recurrence Reporting Research Resistance Respiration Signal Transduction Skeleton Starvation Structure Testing Therapeutic Time Tissues Toxic effect Tumor Tissue Work Xenograft Model anti-cancer base benzothiazole blood-brain barrier crossing blood-brain barrier penetration cancer cell cancer type clinically relevant cytotoxic cytotoxicity design drug candidate efficacy study esterase expectation fenofibric acid improved in silico in vitro testing ketogenic diet mitochondrial membrane monolayer novel therapeutics prototype response scaffold standard of care temozolomide tumor

项目摘要

Glioblastomas are very aggressive tumors of the central nervous system (CNS) with a median patient survival of about 16 months. Therapeutic options for glioblastoma patients are very limited mostly because the majority of potential anti-cancer drugs do not cross the blood brain barrier (BBB). In addition, recently tested immunotherapies including immune checkpoint inhibitors, tumor vaccines, and adoptive cell therapies failed to produce a positive outcome in glioblastoma patients. Surprisingly, metabolic approaches including calorie restriction and ketogenic diet demonstrate promising results as supplemental therapies for glioblastoma patients. In this regard, multiple studies, including our research, show that a common lipid-lowering prodrug, fenofibrate (FF), triggers a severe energetic crisis in glioblastoma cells by compromising the function of Complex 1 of the electron transport chain (ETC), leading to the extensive glioblastoma cell death. However, FF does not cross the BBB and is quickly processed by blood and tissue esterases to fenofibric acid, which is a potent PPARµ agonist, no longer effective in killing glioblastoma cells. Therefore, we have made several chemical modifications in the FF molecular skeleton to construct a new family of drugs with high anti-glioblastoma potential. In this proposal, we attempt to test the overall hypothesis that specific chemical modification/s in the common molecular skeleton of FF, benzyl-phenoxy-acetamide (BPA), will result in a new anti-glioblastoma metabolic drug/s that are stable, capable of crossing the BBB, and effective in triggering glioblastoma cell death at low µM concentrations. Our preliminary results indicate that two new drug candidates designated here, as MT1 and MT3, have very promising characteristics for BBB penetration. To evaluate these compounds, we have developed a comprehensive experimental approach consisting of: a) computational modeling of the BPA molecular structure by applying the Central Nervous System – Multiparameter Optimization (CNS-MPO) algorithm; b) development of the most effective strategy for synthesis and testing of chemical integrity and purity of the new compound; c) in vitro testing for glioblastoma cytotoxicity and the mechanism of action; and d) Pharmacokinetic analyses of the compound bioavailability, maximal tolerated dose (MTD) and anti-glioblastoma efficacy in highly relevant animal models.

胶质母细胞瘤是一种侵袭性极强的中枢神经系统 (CNS) 肿瘤，患者中位生存率较低胶质母细胞瘤患者的治疗选择非常有限，因为大多数患者的治疗时间约为 16 个月。此外，最近的测试表明，潜在的抗癌药物不会穿过血脑屏障（BBB）。包括免疫检查点抑制剂、肿瘤疫苗和过继性细胞疗法在内的免疫疗法未能令人惊讶的是，包括热量在内的代谢方法对胶质母细胞瘤患者产生了积极的结果。限制饮食和生酮饮食作为胶质母细胞瘤患者的补充疗法显示出有希望的结果。在这方面，包括我们的研究在内的多项研究表明，一种常见的降脂前药非诺贝特 (FF)，通过损害胶质母细胞瘤细胞复合物 1 的功能，引发严重的能量危机电子传递链（ETC），导致胶质母细胞瘤细胞广泛死亡，然而，FF不跨越该链。 BBB 并被血液和组织酯酶快速加工成非诺贝酸，非诺贝酸是一种有效的 PPARμ 激动剂，不再有效杀死胶质母细胞瘤细胞，因此，我们对其进行了一些化学修饰。 FF分子骨架构建了具有高抗胶质母细胞瘤潜力的新药物家族。我们试图检验共同分子骨架中特定化学修饰的总体假设 FF，苯甲基苯氧基乙酰胺（BPA），将产生一种新的稳定的抗胶质母细胞瘤代谢药物，能够穿过 BBB，并在低 µM 浓度下有效触发胶质母细胞瘤细胞死亡。初步结果表明，这里指定的两种新药候选物，MT1和MT3，具有非常好的前景为了评估这些化合物的 BBB 渗透特性，我们开发了一种全面的方法。实验方法包括：a) 通过应用以下方法对 BPA 分子结构进行计算建模 b) 中枢神经系统-多参数优化（CNS-MPO）算法；合成和测试新化合物的化学完整性和纯度的有效策略 c) 体外测试；胶质母细胞瘤细胞毒性和作用机制；和 d) 化合物的药代动力学分析；在高度相关的动物模型中的生物利用度、最大耐受剂量（MTD）和抗胶质母细胞瘤功效。