CLFB143 Analogs to Treat Glaucoma

治疗青光眼的 CLFB143 类似物

• 批准号: 8644961
• 负责人: Val S. Goodfellow
• 金额: $ 22.38万
• 依托单位: CALIFIA BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644961
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Abbreviations; Active Sites; Adverse effects; Animal Model; Animals; Apoptosis; Apoptotic; Back; Binding; Biochemical; Biological Assay; Biology; Blindness; Blood; Brain; Cause of Death; Cell Death; Cell Death Process; Cell Survival; Cells; Cessation of life; Collaborations; Collection; Complement; Cytoprotection; Data; Development; Disease; Dose; Drug Formulations; Drug Kinetics; Equilibrium; Exhibits; Eye; Eyedrops; Family; Foundations; Genes; Glaucoma; Goals; HIV; Health; Human; Image; In Vitro; Individual; Intellectual Property; JUN gene; Kinetics; Knockout Mice; Laser Surgery; Lead; Leucine Zippers; Libraries; Ligand Binding; Literature; Liver Microsomes; MAP Kinase Gene; MAPK8 gene; Modeling; Molecular; Mus; Nerve Crush; Nerve Degeneration; Neurites; Neurocognitive; Neurodegenerative Disorders; Neurons; Neuropathy; Neuroprotective Agents; Optic Nerve; Pathway interactions; Patients; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phosphotransferases; Physiologic Intraocular Pressure; Positioning Attribute; Property; Protein Kinase; Protein Kinase Inhibitors; Publishing; RNA Interference; Radio; Reaction; Research; Retina; Retinal Ganglion Cells; Risk; Role; Safety; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Small Interfering RNA; Solubility; Specificity; Structure; Sutent; Testing; Toxic effect; Toxicology; United States National Institutes of Health; Universities; Vision; analog; base; cell injury; commercialization; design; efficacy testing; feeding; improved; in vitro Assay; in vitro activity; in vivo; in vivo Model; inhibitor/antagonist; injured; kinase inhibitor; lead series; mixed lineage kinase 3; neurotoxicity; novel; pharmacophore; protein kinase inhibitor; public health relevance; research clinical testing; scaffold; screening; small molecule; small molecule libraries; stress-activated protein kinase 1

Project Summary Glaucoma is the leading cause of irreversible blindness worldwide. In glaucoma, retinal ganglion cells (RGCs), the projection neurons that transmit vision from the retina to the brain, are injured and die, partially as a result of increased intraocular pressure (IOP). Current therapies (laser, surgery and eye drops) all act by lowering IOP. Unfortunately, lowering IOP can produce undesirable side effects and/or be difficult to achieve. Moreover, in some patients, RGC loss continues despite significant IOP reduction. Lacking are "neuroprotective" agents that directly interfere with the cell death process in RGCs. The development of safe and efficacious neuroprotective agents would improve glaucoma therapy by complementing the currently available IOP treatment options. In order to identify such compounds, the Zack group at Johns Hopkins developed a high- content, high-throughput small molecule screen using RGCs. This takes advantage of the ability to isolate and culture primary murine RGCs and then uses automated fluorescent imaging and biochemical assays to screen through small molecule libraries in order to identify compounds that promote RGC survival and neurite outgrowth. Through this screen broad-spectrum protein kinase inhibitors such as Sutent and VX-680 were identified as neuroprotective. Unfortunately the identified compounds are weakly active and extremely toxic. To parse out the individual kinases responsible for cell death and survival, an RNA interference-based approach was utilized. Our collaborators at Johns Hopkins adapted their primary RGC platform for high- throughput siRNA-based screening and used it to screen an arrayed library of siRNAs targeting the mouse kinome. The top two hits identified (i.e. genes whose knockdown promoted survival) were a little explored kinase, DLK and its substrate, MKK7. Independently, Califia Bio has designed and synthesized drug-like inhibitors of this protein kinase target for potential treatment of neuropathy. Potent Califia Bio DLK inhibitors are very active in the Johns Hopkins' RGC protection assay. We have identified a potential lead series from several screening hits from a Califia Bio proprietary scaffold. We present a medicinal chemistry plan and screening cascade to optimize these screening hits into advanced lead compounds with appropriate in vitro PK profiles for direct dosing to the eye to minimize systemic toxicity risk and limited off-target activity. Compounds will be optimized to provide sufficient drug like molecules for preliminary efficacy tests in animals. In phase two, we will optimize compounds for ocular delivery formulations, pharmacokinetic properties, in vivo activity and characterize them in preliminary toxicology and geneotoxicity assays.

项目摘要 青光眼是全球不可逆失明的主要原因。在青光眼，视网膜神经节细胞（RGC）中， 结果，将视觉从视网膜传播到大脑的投射神经元部分受伤并死亡 眼内压力（IOP）的增加。当前疗法（激光，手术和眼部滴）均通过降低 IOP。不幸的是，降低IOP会产生不良的副作用和/或难以实现。而且， 在某些患者中，尽管IOP大幅降低，但RGC损失仍在继续。缺乏“神经保护剂” 直接干扰RGC中的细胞死亡过程。安全有效的发展 神经保护剂将通过补充当前可用的IOP来改善青光眼治疗 治疗选择。为了识别此类化合物，约翰·霍普金斯（Johns Hopkins）的Zack组开发了高度 内容，使用RGC的高通量小分子筛选。这利用了隔离和 培养初级鼠RGC，然后使用自动荧光成像和生化测定 通过小分子库来识别促进RGC存活和神经突的化合物 出生。通过此屏幕，广谱蛋白激酶抑制剂（如Sutent和VX-680）是 被识别为神经保护作用。不幸的是，所鉴定的化合物活跃且极具毒性。 解析负责细胞死亡和生存的单个激酶，这是一种基于RNA的干扰 使用方法。我们在约翰·霍普金斯（John Hopkins）的合作者改编了他们的主要RGC平台 基于吞吐量的siRNA筛选，并将其用于筛选针对鼠标的siRNA库库 Kinome。确定的前两个命中（即，抑制了促进生存的基因）有点探索 激酶DLK及其底物MKK7。独立地，Califia Bio设计和合成了类似药物 该蛋白激酶靶标的抑制剂用于神经病的潜在治疗。有效的Califia Bio DLK抑制剂 在约翰·霍普金斯（Johns Hopkins）的RGC保护测定中非常活跃。我们已经确定了一个潜在的潜在客户系列 来自Califia Bio专有脚手架的几次筛选。我们提出了一个药物化学计划， 筛查级联 直接给出眼睛的概况，以最大程度地减少系统性毒性风险和有限的脱靶活动。化合物 将优化以提供足够的药物（例如分子）进行动物初步疗效测试。在阶段 第二，我们将优化眼部递送配方，药代动力学特性的化合物，体内活性 并在初步毒理学和基因毒性测定中表征它们。