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

胶质母细胞瘤是中枢神经系统（CNS）的侵袭性非常强的肿瘤，患者的中位生存期 大约16个月。胶质母细胞瘤患者的治疗选择非常有限，主要是因为大多数 潜在的抗癌药物不能穿过血脑屏障（BBB）。此外，最近测试的 包括免疫检查点抑制剂、肿瘤疫苗和过继细胞疗法在内的免疫疗法未能 在胶质母细胞瘤患者中产生积极的结果。令人惊讶的是，包括卡路里在内的代谢方法 限制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复合物1的功能，引发胶质母细胞瘤细胞中严重的能量危机。 电子传递链（ETC），导致广泛的胶质母细胞瘤细胞死亡。然而，FF并没有跨越 血脑屏障，并迅速处理血液和组织酯酶非诺贝酸，这是一种有效的PPAR µ激动剂， 不再有效杀死胶质母细胞瘤细胞。因此，我们对该产品进行了几次化学修饰， FF分子骨架构建具有高抗胶质母细胞瘤潜力的新药物家族。在这一提议中， 我们试图验证一个总体假设，即在普通分子骨架中的特定化学修饰 FF，苄基苯氧基乙酰胺（BPA），将产生一种新的抗胶质母细胞瘤代谢药物， 能够穿过血脑屏障，并在低µ M浓度下有效触发胶质母细胞瘤细胞死亡。我们 初步结果表明，两个新的候选药物，这里指定的MT1和MT3，具有非常有前途的， BBB渗透的特征。为了评估这些化合物，我们开发了一种全面的 实验方法包括：a）通过应用 中枢神经系统-多参数优化（CNS-MPO）算法; B）开发最 用于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 用于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。

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.