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.

2型神经纤维瘤病（NF2）是一种主要遗传的常染色体疾病，最常见 表现是第八个颅神经（前庭造型瘤）的双侧schwannomas的发展。 大多数NF2患者在整个神经系统中都会出现其他肿瘤，包括Schwannomas， 脑膜瘤和室系膜瘤，导致严重的发病率和早期死亡率。 NF2肿瘤抑制基因 编码称为Merlin的69 kDa蛋白，与许多信号通路的调节有关 作为小型G蛋白和河马信号通路的调节。尽管我们对 在过去的二十年中，NF2基础的分子机制有所改善，有效的疗法仍然存在 缺乏。 迄今为止，确定NF2治疗剂的系统努力表现出了有限的成功，导致 在识别少数候选者对NF2缺陷细胞的选择性最小的候选者时。 可以说，这一有限成功的原因源于许多因素，包括这些努力依靠的事实 在使用传统筛查测定法上使用镀塑料上的细胞进行的传统筛选测定，在2-中 尺寸（2D）单层格式。这些疾病反映了环境细胞在体内经历的经历。 此外，对先前的一小部分化合物进行了先前的筛选 基于吸毒，已知的药理学，调节状态等。因此，只有有限的化学空间才有 在这些努力中探讨了。 我们的长期目标是确定有选择地抑制NF2-null Schwann细胞并优化的小分子 这些成铅分子将发展为治疗剂。达到这个目标，我们将实施 筛选活动结合了我们已经急剧证明的许多创新 改善发现工作。我们假设拟议的研究活动将在药理上确定 NF2无效细胞中的可处理靶/途径，将作为治疗发育的铅开发。