HEAL: Probe/Drug Lead Production

HEAL：探针/先导药物生产

• 批准号: 10255305
• 负责人: Matthew Hall
• 金额: $ 226.27万
• 依托单位: NATIONAL CENTER FOR ADVANCING TRANSLATIONAL SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10255305
• 关键词: 3-Dimensional; Absence of pain sensation; Abstinence; Address; Agonist; Analgesics; Animal Model; Animals; Antibodies; Biological Assay; Biological Availability; Biological Models; Biology; Blood - brain barrier anatomy; Brain; Cell Membrane Permeability; Cell model; Cells; Chemicals; Chemistry; Chemotherapy-induced peripheral neuropathy; Chronic inflammatory pain; Clinic; Clinical; Clinical Trials; Collaborations; Complex; Coupled; Data; Development; Disease; Dose; Drug Kinetics; Drug Screening; Effectiveness; Enzymes; Extramural Activities; FOLH1 gene; G-Protein-Coupled Receptors; Galanin; Galectin 1; Genes; Genomics; Glutamates; Goals; Habenula; Health; Human; Human Biology; Hydrolysis; Hyperalgesia; Immune system; Individual; Inflammatory; Infrastructure; Inherited; Intervention; Investigational Drugs; Ion Channel; Ion Channel Gating; Joints; Knockout Mice; Lead; Libraries; Ligands; Link; Literature; Mechanoreceptors; Medial; Mediating; Membrane; Methodology; Methods; Midbrain structure; Migraine; Modeling; Modernization; Molecular; Molecular Target; N-acetylaspartate; Nature; Neuraxis; Neuronal Plasticity; Neurons; Neuropeptides; Opiate Addiction; Opioid; Oral; Orphan; Overdose; Pain; Pain management; Patients; Penetration; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physiology; Play; Pre-Clinical Model; Process; Production; Pruritus; Public Health; Quality of life; Research; Research Project Grants; Resources; Rewards; Risk; Role; Science; Sodium Channel; Source; Spinal Cord; Stretching; Substance P; System; Tactile; Testing; Therapeutic Intervention; Tissue Microarray; Tissues; Touch sensation; Translational Research; Translations; United States Food and Drug Administration; United States National Institutes of Health; Validation; Work; Zinc; addiction; adenylyl cyclase 1; allodynia; base; bioprinting; chronic itch; chronic pain; clinical candidate; design; drug candidate; druggable target; effective therapy; efficacy study; extracellular; first-in-human; high throughput screening; human model; human subject; improved; induced pluripotent stem cell; inhibitor/antagonist; innovation; insight; lead series; loss of function; loss of function mutation; mechanical allodynia; metalloenzyme; mu opioid receptors; neural circuit; nociceptin; non-opioid analgesic; novel; novel therapeutic intervention; novel therapeutics; opioid epidemic; opioid misuse; opioid overdose; opioid use; opioid use disorder; pain processing; pain sensation; painful neuropathy; pre-clinical; preclinical development; preclinical efficacy; preclinical study; prevent; receptor; response; safety study; screening; serotonin 7 receptor; serotonin receptor; small molecule; small molecule inhibitor; small molecule libraries; success; tool; transmission process; virtual

HEAL Compound Library ETB has created a comprehensive annotated HEAL library of compounds including drugs, probes, and tool compounds for addiction and pain relevant targets. The modern nature of the HEAL target and compound library incorporates years of valuable sources and lessons learned on high-throughput screening and chemical library design at NCATS. A screening-ready library of HEAL compounds, available through collaborative efforts, allows rapid strategic screening for drug repurposing, innovative profiling, and hypothesis testing of novel targets and tool compounds, thus fast tracking efforts to develop novel pharmacotherapies for pain, addiction, and overdose. Development of Gpr151 Modulators for the Treatment of Opioid Dependence This collaboration seeks to develop novel Gpr151 modulators to facilitate long-term abstinence in opioid-dependent individuals. Gpr151 is an orphan G-protein coupled receptor (GPCR) that is expressed in the central nervous system and immune system as well. It is also expressed in the medial habenula. The project team will confirm assay robustness and reliability (z values; assay window, etc.) suitable to initiate high-throughput small molecule screen against Gpr151 and then execute HTS screen against Gpr151. The team will confirm activity of the most promising hits from HTS using six-point dose-response curves in primary screen and confirmation of activity in secondary screens. Probe development, GPCR profiling, and ADME/PK will be done at NCATS, while leads will be tested in an opioid dependence model in the collaborators lab. Optimization of Allosteric Regulators of the NaV1.7 Sodium Channel for Chemotherapy-induced Peripheral Neuropathy (CIPN) Long-term use of opioids to treat chronic pain caused by chemotherapy-induced peripheral neuropathy (CIPN) can result in tolerance and addiction amongst other health problems. There is a distinct need for safe, effective, and non-addictive drugs with novel mechanisms of action to help improve quality of life for those that suffer from neuropathic pain. The scope of this project is for NCATS and the collaborative team to optimize the novel lead series compounds of allosteric regulators of the Nav1.7 sodium channel identified from a virtual screen campaign, such that one lead reaches the stage of a clinical candidate. This collaboration addresses the HEAL Initiatives goal to develop a novel, non-opioid target for chronic pain. High Throughput Screen to Identify Glutamate Carboxypeptidase II (GCPII) Brain-Penetrable-Inhibitors for the Treatment of Pain Glutamate carboxypeptidase II (GCPII) is a membrane-bound, zinc metalloenzyme that catalyzes the hydrolysis of the abundant neuropeptide N-acetyl-aspartate-glutamate (NAAG) to N-acetyl-aspartate (NAA) and glutamate. Inhibition of GCPII in the brain results in both increased extracellular NAAG and decreased extracellular glutamate. These effects diminish glutamate transmission, which has been associated with pain sensation and transmission. Previous studies indicated that GCPII inhibition would be a viable approach to treating pain; however, the GCPII inhibitors evaluated to date have not moved into the clinic because of poor brain penetration, low oral bioavailability, and low membrane permeability. These limitations will be addressed by the collaborative team as they focus on the identification of small molecule inhibitors of GCPII that penetrate the brain for the treatment of pain. Adenylyl Cyclase 1 (AC1) Inhibitors as Opioid Alternatives for Chronic and Inflammatory Pain Neuronal adenylyl cyclase type I (AC1) is an enzyme that is highly expressed in neuronal tissues associated with pain processing and neuronal plasticity. Preclinical studies have shown that AC1 could be a promising target to treat chronic and inflammatory pain. Additional research in AC1 knockout mice suggested that an absence of AC1 reduced the rewarding effects of opioids and opioid dependence. Despite promising observations in the literature, there is a need to further explore and validate AC1 as a pain target. The collaborative project will focus on the development and mechanistic characterization of AC1selective, central nervous system (CNS) penetrant small molecule inhibitors as a novel, nonopioid treatment for chronic pain. 5-HT7 Receptor Agonists as Novel Treatments for Pain, Opioid-Induced Hyperalgesia, and Opioid Use Disorder Studies have shown that the G-coupled 5-HT7 serotonin receptor (5-HT7R) is a novel molecular target for pain, and several 5-HT7R agonists have been identified in the literature; however, these agonists are largely understudied, and it is unclear why they havent been developed further. The joint research project aims to address this gap by evaluating known 5-HT7R agonists and furthering their preclinical development through pharmacokinetic studies. Identification of Brain-Permeant Small Molecule Modulators of GAL1R Receptor Mu-opioid receptors (MOR) mediate both the analgesic and addictive effects of opioids. Galanin, a neuropeptide, exerts analgesic effects by acting on galanin Gal1 receptors (Gal1R) localized in the spinal cord. Dr. Ferre discovered that galanin counteracts the addictive effects of opioids by acting on Gal1R that forms complexes (heteromers) with MOR localized in the mesencephalon; additionally, Gal1R mediates the dopaminergic effects of opioids. The project aims to discover potent and selective Gal1R ligands with the ability to cross the blood-brain barrier, which could provide strong analgesia with low abuse liability when combined with opioids. The project combines the collaborative teams expertise and capabilities of implementing state-of the art methods to obtain new compounds for druggable targets, including high-throughput screening (HTS), medicinal chemistry, and biological models of analgesia and opioid reward. Chemical Modulators of the PIEZO2 Mechanoreceptor for the Study and Treatment of Pain The stretch-gated ion channel PIEZO2 has recently been identified as a novel pain target. Human subjects with inherited loss of function mutations in this gene fail to develop mechanical allodynia, a very common type of chronic pain whereby normally innocuous touch becomes painful. These findings suggest that topical PlEZO2 antagonists may be effective for treating this type of pain. Additionally, PIEZO2 loss of function has been linked to chronic itch, suggesting that topical PIEZO2 agonist may be effective for itch treatment. The goal of this collaboration is to develop high throughout screens to discover and characterize small molecule probes of the mechanosensory ion channels PIEZO2. Validated hits will be optimized, and leads will be tested in animal models to demonstrate target engagement and efficacy. The overall goal is to develop a novel therapeutic approach for treating tactile allodynia. Substance P Antibody Development Blocking the interaction between inflammatory neuropeptides and their receptors is a promising approach for treating chronic pain and migraine. Small molecule antagonists have failed due to multiple receptors per peptide; however, there has been success using antibodies to block the function of CGRP, an inflammatory neuropeptide, to reduce or even prevent migraine attacks. Unfortunately, these antibodies do not get across the blood-brain barrier (BBB), which limits their effectiveness. There are several other neuropeptides known to contribute to chronic pain, such as substance P, Tac 1, and Nociceptin. This collaborative project aims to develop cell-based assays and identify BBB penetrant, functional antibodies to neuropeptides known to play roles in chronic pain and migraine. Findings from this project will have a significant impact by identifying new, non-addictive, and effective treatments for chronic pain and migraine.

治愈复合库 ETB创建了一个全面的注释愈合文库，包括吸毒和疼痛相关靶标的药物，探针和工具化合物。 Heal目标和复合库的现代性质结合了多年的宝贵资源和在NCAT的高通量筛查和化学库设计中学到的经验。可通过协作努力获得的筛查库库，可以快速进行战略性筛查，以重新利用药物，创新分析以及对新目标和工具化合物的假设测试，从而快速跟踪为开发新颖的疼痛，成瘾和过量药物治疗的药物治疗。 GPR151调节剂的开发用于治疗阿片类药物依赖性 这项合作旨在开发新型的GPR151调节剂，以促进阿片类药物依赖性个体的长期禁欲。 GPR151是一种在中枢神经系统和免疫系统中表达的孤儿G蛋白偶联受体（GPCR）。它也在内侧Habenula中表达。 项目团队将确认适用于GPR151的高通量小分子屏幕，然后针对GPR151执行HTS屏幕。该团队将使用六点剂量响应曲线在主屏幕中确认HTS最有希望的击中的活动，并确认次级筛选中的活动。探针开发，GPCR分析和ADME/PK将在NCATS进行，而Leads将在协作者实验室的阿片类药物依赖模型中进行测试。 NAV1.7化学疗法诱导的周围神经病（CIPN）NAV1.7钠通道的变构调节剂的优化 长期使用阿片类药物来治疗化学疗法引起的周围神经病（CIPN）引起的慢性疼痛，可能会导致其他健康问题之间的耐受性和成瘾性。对于那些患有神经性疼痛的人来说，采取新颖的作用机制，需要采取新颖的作用机理，以帮助改善生活质量，这明显需要安全，有效和非添加性药物。该项目的范围是NCAT和协作团队，以优化从虚拟屏幕活动中确定的NAV1.7钠渠道的变构调节器的新型铅系列化合物，从而使一个铅是临床候选者的阶段。这项合作解决了HEAL计划的目标，以开发出一种新型的，非阿片类药物的慢性疼痛靶标。 高吞吐量屏幕以鉴定谷氨酸羧肽酶II（GCPII）可用于治疗疼痛的脑抑制剂 谷氨酸羧肽酶II（GCPII）是一种膜结合的锌金属酶，可催化丰富的神经肽N-乙酰基天冬氨酸 - 谷氨酸（NAAG）的水解为N-乙酰基天冬氨酸（NAA）（NAA）和glutamate。 GCPII在大脑中的抑制会导致细胞外NAAG增加和细胞外谷氨酸的降低。这些影响减少了谷氨酸的传播，这与疼痛感觉和传播有关。先前的研究表明，GCPII抑制作用将是治疗疼痛的可行方法。但是，迄今为止评估的GCPII抑制剂由于脑穿透不良，口服生物利用度低和膜渗透性低而尚未进入诊所。协作团队将解决这些局限性，因为它们专注于识别GCPII的小分子抑制剂，该抑制剂穿透了大脑以治疗疼痛。 腺苷酸环化酶1（AC1）抑制剂作为慢性和炎症性疼痛的阿片类药物替代品 神经腺苷酸环化酶I型（AC1）是一种在与疼痛加工和神经元可塑性相关的神经元组织中高度表达的酶。临床前研究表明，AC1可能是治疗慢性和炎症性疼痛的有希望的靶标。 AC1敲除小鼠的其他研究表明，缺乏AC1会降低阿片类药物和阿片类药物依赖性的奖励作用。尽管文献中有希望的观察结果，但仍有必要进一步探索和验证AC1作为疼痛靶标。该协作项目将重点介绍AC1选择性，中枢神经系统（CNS）渗透性小分子抑制剂的发育和机理表征，作为一种新型的非阿片类药物治疗，用于慢性疼痛。 5-HT7受体激动剂作为疼痛，阿片类药物诱导的痛觉过敏和阿片类药物使用障碍的新型治疗方法 研究表明，G偶联的5-HT7 5-羟色胺受体（5-HT7R）是疼痛的新分子靶标，在文献中已经鉴定出了几种5-HT7R激动剂。但是，这些激动剂在很大程度上被研究了，目前尚不清楚为什么他们还没有进一步发展。联合研究项目旨在通过评估已知的5-HT7R激动剂并通过药代动力学研究来促进其临床前发展，以解决这一差距。 鉴定GAL1R受体的脑渗透小分子调节剂 MU-阿片类受体（MOR）介导阿片类药物的镇痛和成瘾作用。神经肽Galanin通过作用于脊髓中定位的Galanin Gal1受体（GAL1R）来发挥镇痛作用。 Ferre博士发现，Galanin通过作用于与MOR位于中脑中的MOR形成复合物（异源）的GAL1R来抵消阿片类药物的成瘾作用。此外，GAL1R介导阿片类药物的多巴胺能作用。该项目旨在发现具有跨越血脑屏障的能力的有效和选择性的GAL1R配体，当与阿片类药物结合使用时，这可能会提供强大的镇痛责任。该项目结合了实施最先进方法的协作团队的专业知识和能力，以获取针对可药物目标的新化合物，包括高通量筛查（HTS），药物化学和镇痛和阿片类奖励的生物学模型。 压电2机械受体的化学调节剂，用于研究和治疗疼痛 拉伸门控的离子通道压电2最近被确定为一种新的疼痛靶标。该基因中遗传功能突变丧失的人类受试者无法发展机械性异常性痛，这是一种非常普遍的慢性疼痛类型，通常无害的触摸会变得痛苦。这些发现表明，局部plezo2拮抗剂可能有效地治疗这种疼痛。此外，功能的压电丧失与慢性瘙痒有关，这表明局部压电激动剂可能对瘙痒治疗有效。这种合作的目的是在整个屏幕中发展高度，以发现和表征机械感觉离子通道Piezo2的小分子探针。经过验证的命中将得到优化，并将在动物模型中测试铅，以证明目标参与和功效。总体目标是开发一种新型的治疗方法来治疗触觉异常。 物质P抗体发育 阻止炎症性神经肽及其受体之间的相互作用是治疗慢性疼痛和偏头痛的一种有前途的方法。小分子拮抗剂由于每个肽多个受体而失败。但是，使用抗体已经成功地阻断了炎症性神经肽CGRP的功能，以减少甚至预防偏头痛攻击。不幸的是，这些抗体并未跨越血脑屏障（BBB），这限制了它们的有效性。还有其他几种神经肽会导致慢性疼痛，例如P，TAC 1和Nocceptin。该协作项目旨在开发基于细胞的测定法，并确定已知在慢性疼痛和偏头痛中扮演角色的神经肽的功能抗体。该项目的发现将通过识别新的，非依恋的慢性疼痛和偏头痛的有效治疗方法，从而产生重大影响。