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: 10401628
• 负责人: JOSEPH KISSIL
• 金额: $ 28.96万
• 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: 2021-05-05 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401628
• 关键词: 3-Dimensional; Acoustic Neuroma; Affinity; Benchmarking; Bilateral; Biological Assay; Cell Culture Techniques; Cell Survival; Cells; Characteristics; Chemicals; Collection; Cranial Nerves; Development; Disease; Environment; Ependymoma; Exposure to; Funding; Generations; Goals; Growth; Human; Inherited; Intervention; Knowledge; Lead; Libraries; Ligands; Methods; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Nervous system structure; Neurilemmoma; Neurofibromatosis 2; Neurofibromin 2; Null Lymphocytes; Operative Surgical Procedures; Pathway interactions; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Proteins; Proteome; Proteomics; Radiation therapy; Regulation; Research; Schwann Cells; Signal Pathway; Symptoms; Technology; Therapeutic; Therapeutic Agents; Tumor Suppressor Genes; Validation; analog; base; bevacizumab; cell growth; cytotoxic; drug development; drug discovery; effective therapy; experience; improved; in vivo; in vivo Model; innovation; loss of function; meningioma; monolayer; mortality; nervous system disorder; new therapeutic target; preclinical development; programs; screening; small molecule; small molecule inhibitor; small molecule libraries; stem; success; therapeutic development; tumor; two-dimensional

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(NF2)是一种主要遗传的常染色体疾病，是最常见的 临床表现为双侧第8颅神经鞘瘤(前庭神经鞘瘤)。 大多数NF2患者在整个神经系统都会发生额外的肿瘤，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。NF2抑癌基因 编码一种名为Merlin的69 kDa蛋白质，参与调节许多信号通路，如 受小G蛋白和Hippo-Yap信号通路的调控。虽然我们对此的理解 NF2的分子机制在过去20年中得到了改善，有效的治疗方法仍然存在 缺乏。 到目前为止，寻找NF2治疗药物的系统努力显示出有限的成功，结果 在鉴定对NF2缺乏的细胞表现出最小选择性的少数候选细胞中。 可以说，这种有限成功的原因源于许多因素，包括这些努力所依赖的事实 利用塑料培养皿上的细胞进行传统筛选分析的方法，在2- 维(2D)单层格式。这些条件不能很好地反映细胞在体内所经历的环境。 此外，之前的筛选是针对一小部分预先选择的化合物进行的 基于药物的相似性、已知的药理作用、调节状态等，因此，只有有限的化学空间 在这些努力中进行了探索。 我们的长期目标是识别选择性抑制NF2缺失的雪旺细胞的小分子，并优化 这些物质转化成铅分子，将被开发成治疗剂。为了实现这一目标，我们将实施 结合了我们已经戏剧性地展示的许多创新的筛选活动 改进发现工作。我们假设，拟议的研究活动将从药理上确定 NF2缺失细胞中易于处理的靶点/途径，将被开发为治疗开发的先导。