Development of small molecule Limk inhibitors for probing ocular diseases

开发用于探测眼部疾病的小分子 Limk 抑制剂

• 批准号: 8166343
• 负责人: Yangbo Feng
• 金额: $ 29.7万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8166343
• 关键词: Actin-Binding Protein; Actins; Adverse effects; Alzheimer' s Disease; Benzimidazoles; Biochemical; Biological Assay; Biological Process; Biology; Brain; Cells; Central Nervous System Diseases; Development; Disease; Evaluation; Eye; Glaucoma; Goals; Inflammation; Inhibitory Concentration 50; Intracranial Aneurysm; Malignant Neoplasms; Microtubules; Molecular; Molecular Probes; Neuraxis; Pathway interactions; Peer Review; Penetration; Pharmaceutical Preparations; Phosphorylation; Phosphotransferases; Physiologic Intraocular Pressure; Property; Protein Isoforms; Protein-Serine-Threonine Kinases; Public Health; Publications; Reporting; Research; Rho-associated kinase; Screening procedure; Signal Transduction; Solubility; Williams Syndrome; actin depolymerizing factor; base; benzimidazole; cofilin; design; drug discovery; inhibitor/antagonist; kinase inhibitor; novel; polymerization; primary pulmonary hypertension; scaffold; small molecule; therapy development; tool

DESCRIPTION (provided by applicant): Lim kinases (Limk) are serine/threonine kinases which regulate microtubule stability and actin polymerization by phosphorylation and inactivation of actin binding proteins, the actin depolymerizing factor (ADF) and cofilin. The abnormal expression of either Limk isoform, Limk1 or Limk2, is implicated in numerous malfunctions that are related to a variety of diseases, such as glaucoma, ocular inflammation, cancer, primary pulmonary hypertension, intracranial aneurysms, Alzheimer's disease, and Williams syndrome. Lim kinases are downstream effectors of Rho kinases (ROCK). ROCK inhibitors have been demonstrated to be effective in reducing intraocular pressure (IOP) in recent years, and it is believed that this effect of ROCK inhibitors is through the Limk pathway. Unlike Rho kinases which have multiple substrates, Lim kinases serve as points of signal integration and channel this information to a select few substrates, which makes Lim kinases good targets for drug discovery with much less potential side effects. Despite the attractive potential of Limk inhibitors, there have been no small molecule inhibitors reported in peer-reviewed publications which showed simultaneously good potency, high selectivity, good solubility and appropriate DMPK properties for ocular and/or other CNS applications (such as good eye and/or brain penetration properties). In this application, we propose to develop novel small molecule Limk inhibitors based on a benzimidazole scaffold. Through the synthesis and evaluation of approximately 100 compounds total in two years, we anticipate discovering Limk inhibitors with biochemical IC50 values of < 20 nM, cell-based IC50 values of < 200 nM, good selectivity, excellent solubility, and with good eye and/or brain penetration properties. These compounds will serve as useful molecular tools to study the biological functions of Limk, and to probe ocular diseases and other Limk related CNS diseases. ) PUBLIC HEALTH RELEVANCE: The relevance of this project to public health is that it will provide useful tools to study ocular diseases and other central nervous system (CNS) diseases. Specifically, this research will discover potent and selective inhibitors of Lim kinase (Limk), which will be used as molecular probes to investigate Limk biology in the development and treatment of ocular diseases (glaucoma and ocular inflammation) and likely other Limk related CNS diseases. Eventually these probes can be used to facilitate the discovery of novel drugs to treat glaucoma and ocular inflammation.

描述（由申请人提供）：Lim激酶（Limk）是丝氨酸/苏氨酸激酶，其通过肌动蛋白结合蛋白、肌动蛋白解聚因子（ADF）和cofilin的磷酸化和失活来调节微管稳定性和肌动蛋白聚合。Limk同种型Limk 1或Limk 2的异常表达涉及与多种疾病相关的许多功能障碍，例如青光眼、眼部炎症、癌症、原发性肺动脉高压、颅内动脉瘤、阿尔茨海默病和威廉姆斯综合征。Lim激酶是Rho激酶（ROCK）的下游效应子。近年来，ROCK抑制剂已被证明可有效降低眼内压（IOP），并且认为ROCK抑制剂的这种作用是通过Limk途径。与具有多个底物的Rho激酶不同，Lim激酶充当信号整合点并将此信息引导至选定的少数底物，这使得Lim激酶成为药物发现的良好靶标，具有少得多的潜在副作用。尽管Limk抑制剂具有吸引人的潜力，但在同行评审的出版物中还没有报道同时显示出良好的效力、高选择性、良好的溶解度和用于眼部和/或其他CNS应用的适当DMPK性质（例如良好的眼部和/或脑部渗透性质）的小分子抑制剂。在本申请中，我们提出开发基于苯并咪唑支架的新型小分子Limk抑制剂。通过在两年内合成和评估总共约100种化合物，我们预计会发现Limk抑制剂，其生物化学IC 50值< 20 nM，基于细胞的IC 50值< 200 nM，具有良好的选择性，优异的溶解性，并具有良好的眼和/或脑渗透性能。这些化合物将作为有用的分子工具，研究Limk的生物学功能，并探测眼部疾病和其他Limk相关的中枢神经系统疾病。) 公共卫生关系：该项目与公共卫生的相关性在于，它将为研究眼部疾病和其他中枢神经系统（CNS）疾病提供有用的工具。具体来说，这项研究将发现有效和选择性的Lim激酶（Limk）抑制剂，这将被用作分子探针，以研究Limk生物学在眼部疾病（青光眼和眼部炎症）和其他可能的Limk相关CNS疾病的发展和治疗。最终，这些探针可用于促进治疗青光眼和眼部炎症的新药的发现。