Employing functionalized fragment libraries to identify therapeutic agents for neurofibromatosis type 2

利用功能化片段库来鉴定 2 型神经纤维瘤病的治疗药物

• 批准号: 10704416
• 负责人: JOSEPH KISSIL
• 金额: $ 41.57万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10704416
• 关键词: Employing; functionalized; fragment; libraries; identify

Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease with the most common manifestation being development of bilateral schwannomas of the 8th cranial nerve (Vestibular schwannoma). The majority of NF2 patients develop additional tumors throughout the nervous system, including schwannomas, meningiomas and ependymomas, causing severe morbidity and early mortality. The NF2 tumor suppressor gene encodes for a 69-kDa protein called Merlin, implicated in the regulation of a number of signaling pathways, such as those regulated by small G-proteins and the Hippo-YAP signaling pathway. Although our understanding of the molecular mechanisms underlying NF2 has improved over the past two decades, effective therapies remain lacking. To date, systematic efforts to identify therapeutic agents for NF2 have demonstrated limited success, resulting in identification of a small number of candidates that displayed minimal selectivity towards NF2-deficient cells. Arguably, the reasons for this limited success stem from a number of factors including the fact these efforts relied on approaches utilizing traditional screening assays performed with cells plated on plastic dishes, in 2- dimensional (2D) monolayer formats. These conditions poorly reflect the environment cells experience in vivo. In addition, previous screens were performed against a small collection of compounds that were pre-selected based on drug-likeness, known pharmacology, regulatory status, etc. Thus, only limited chemical space has been explored in these efforts. Our long-term goals are to identify small molecules that selectively inhibit NF2-null Schwann cells and optimize these into lead molecules that will be developed into therapeutic agents. Towards this goal we will implement a screening campaign that incorporates a number of innovations that we already demonstrated to dramatically improve discovery efforts. We hypothesize that the proposed research campaign will identify pharmacologically tractable targets/pathways in NF2-null cells, which will be developed as leads for therapeutic development.

神经纤维瘤病2型（NF 2）是一种显性遗传的常染色体疾病， 表现为双侧第8脑神经鞘瘤（前庭神经鞘瘤）的发展。 大多数NF 2患者在整个神经系统中发生其他肿瘤，包括神经鞘瘤， 脑膜瘤和室管膜瘤，造成严重的发病率和早期死亡率。NF 2肿瘤抑制基因 编码一种69 kDa的蛋白质，称为Merlin，涉及许多信号通路的调节，如 如由小G蛋白和Hippo-YAP信号通路调节的那些。尽管我们对 在过去的二十年中，NF 2的分子机制得到了改善，有效的治疗方法仍然存在 缺乏 迄今为止，鉴定NF 2治疗剂的系统性努力已经证明了有限的成功， 在鉴定少量对NF 2缺陷细胞显示最小选择性的候选物中。 可以说，这种有限的成功的原因源于一些因素，包括这些努力依赖于 在利用传统的筛选分析方法进行细胞接种在塑料皿上，在2- 三维（2D）单层形式。这些条件很难反映细胞在体内经历的环境。 此外，先前的筛选是针对预先选择的一小部分化合物进行的 基于药物相似性、已知药理学、监管状态等。因此，只有有限的化学空间 在这些努力中得到了探索。 我们的长期目标是确定选择性抑制NF 2缺失的雪旺细胞的小分子，并优化其表达。 将这些转化为先导分子，这些先导分子将被开发成治疗剂。为了实现这一目标，我们将实施一项 筛选活动，其中包括一些创新，我们已经证明，以显着 改进发现工作。我们假设，拟议的研究活动将确定 在NF 2无效细胞中的易处理的靶点/途径，其将被开发为治疗开发的先导。