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，通过磷酸化和肌动蛋白结合蛋白的失活，肌动蛋白去聚合因子（ADF）和辅助蛋白来调节微管稳定性和肌动蛋白聚合。肢体同工型，limk1或limk2的异常表达与许多与多种疾病有关的故障，例如青光眼，眼部炎症，癌症，癌症，原发性肺动脉瘤，颅内动脉瘤，阿尔茨海默氏病，阿尔茨海默氏病以及威廉姆斯综合症。 Lim激酶是Rho激酶（岩石）的下游效应子。近年来，已经证明岩石抑制剂可有效减少眼内压（IOP），并且据信岩石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激酶是信号积分的点，并将此信息引导到精选的少数底物，这使LIM激酶可用于药物发现的良好靶标具有较小的潜在副作用。尽管肢体抑制剂具有吸引人的潜力，但在同行评审的出版物中没有报道过小的分子抑制剂，这些抑制剂同时显示出良好的效能，高选择性，良好的溶解度和适当的眼球和/或其他CNS应用的DMPK特性（例如良好的眼睛和良好的眼睛和良好的眼睛和良好的眼睛）。 /或脑穿透特性）。在此应用中，我们建议基于苯咪唑支架开发新型的小分子limk抑制剂。通过在两年内的大约100种化合物的合成和评估中，我们预计发现具有<20 nm的生化IC50值的肢体抑制剂，基于细胞的IC50值<200 nm <200 nm，良好的选择性，出色的溶解度和良好的眼睛和/或脑穿透特性。这些化合物将用作研究肢体生物学功能，探测眼部疾病和其他肢体相关的中枢神经系统疾病的有用分子工具。 ） 公共卫生相关性：该项目与公共卫生的相关性是，它将为研究眼疾病和其他中枢神经系统（CNS）疾病提供有用的工具。具体而言，这项研究将发现LIM激酶（LIMK）的有效和选择性抑制剂，该抑制剂将用作分子探针，以研究眼部疾病开发和治疗的LIMK生物学（青光眼和眼部炎症）以及其他与limk症相关的CNS疾病。最终，这些探针可用于促进发现新型药物以治疗青光眼和眼部炎症。