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

基本信息

批准号：
8306733
负责人：
Yangbo Feng
金额：
$ 29.7万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8306733
关键词：
Actin-Binding Protein Actins Adverse effects Alzheimer&apos 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

项目摘要

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. )

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）和丝切蛋白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 Limk1 或 Limk2 的异常表达与多种疾病相关的多种功能障碍有关，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) 的下游效应器。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途径实现的。与具有多种底物的 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，且潜在副作用要少得多。尽管 Limk 抑制剂具有吸引人的潜力，但同行评审出版物中尚未报道有小分子抑制剂同时表现出良好的效力、高选择性、良好的溶解度和适合眼部和/或其他中枢神经系统应用的 DMPK 特性（例如良好的眼部和中枢神经系统应用）。 /或大脑穿透特性）。在此应用中，我们建议开发基于苯并咪唑支架的新型小分子 Limk 抑制剂。通过两年内大约100种化合物的合成和评估，我们预计会发现生化IC50值<20nM、细胞IC50值<200nM、良好的选择性、优异的溶解性、良好的眼睛和/或良好的观察性的Limk抑制剂。或大脑渗透特性。这些化合物将作为有用的分子工具来研究 Limk 的生物学功能，并探索眼部疾病和其他 Limk 相关的中枢神经系统疾病。）