Casein Kinase 1 Inhibitors for Treatment of Autism

用于治疗自闭症的酪蛋白激酶 1 抑制剂

• 批准号: 8644557
• 负责人: GRETCHEN L SNYDER
• 金额: $ 34.96万
• 依托单位: INTRA-CELLULAR THERAPIES, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8644557
• 关键词: Address; Affect; Alzheimer' s Disease; Animal Model; Anxiety; Attention deficit hyperactivity disorder; Attenuated; Autistic Disorder; Behavioral; Biological Assay; Biotechnology; Brain; Central Nervous System Diseases; Chemicals; Collaborations; Complex; Confidential Information; Development; Disease; Doctor of Philosophy; Drug Targeting; Engineering; Epigenetic Process; Gene Mutation; Goals; Hyperactive behavior; Impairment; Impulsivity; In Vitro; Individual; Laboratories; Lead; Mediator of activation protein; Molecular Target; Motor Activity; Mus; Nerve Degeneration; Neurodevelopmental Disorder; Penetrance; Permeability; Personal Communication; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phosphotransferases; Pilot Projects; Plasma; Prosencephalon; Protein Isoforms; Protein Kinase; Proteins; Research; Seizures; Sensory; Signal Transduction; Sleep; Sleep Wake Cycle; Small Business Innovation Research Grant; Social Interaction; Staging; Stereotyped Behavior; Symptoms; Testing; Tetracyclines; Therapeutic; Therapeutic Agents; Time; Universities; Work; base; casein kinase I; circadian pacemaker; drug candidate; drug discovery; gastrointestinal; improved; in vivo; inattention; inhibitor/antagonist; innovation; mouse model; novel; novel therapeutics; overexpression; phosphoric diester hydrolase; pre-clinical; programs; public health relevance; small molecule; stereotypy; tau Proteins; tool; trend

PAR-11-133 - PI, Gretchen L. Snyder, PhD Casein Kinase I Inhibitors for Autism Project Summary/Abstract Autism is a neurodevelopmental disorder characterized by abnormal social interaction, deficits in interpersonal communication, and repetitive stereotyped behaviors with a number of individually- occurring associated symptoms, including intellectual impairment, anxiety, seizures, hyperactivity, hyper- or hypo-responsiveness to sensory stimulation, sleep disruption, and gastrointestinal abnormalities. It is noteworthy that hyperactivity, impulsivity, and inattention-core features of attention deficit hyperactivity disorder (ADHD)-occur as associated symptoms in a high percentage (41-78%) of autistic individuals. As a complex, multi-symptom disorder, a large number of gene mutations (heritable and de novo) as well as environmental and epigenetic factors are likely involved in the expression of autism. Currently, there is no cure or satisfactory treatment for autism. New therapeutic agents that would effectively address specific features of the complex disorder would be of high significance and are urgently needed. Casein Kinase 1 (CK1) is a protein kinase target implicated in tau-related neurodegeneration in Alzheimer's disease, in disruption of sleep/wake cycles dictated by the circadian clock, and as a mediator of behavioral hyperactivity. Intra-Cellular Therapies Inc (ITI) is an early-stage pharmaceutical company with an established drug discovery platform and expertise in discovering small- molecule inhibitors for protein phosphodiesterases (PDE1) and protein kinases, like CK1. Our long-time collaborator, Dr. Marc Flajolet of Dr. Paul Greengard's laboratory at The Rockefeller University, has demonstrated that mice engineered to overexpress CK1delta (¿) in a forebrain-restricted, tetracycline- inducible manner (CK1¿OE mice) display behavioral hyperactivity and stereotyped behaviors reminiscent of neurodevelopmental disorders such as autism and ADHD. ITI has identified potent and selective CK1 inhibitors that are orally bio-available, drug-like agents that represent novel chemical entities. Here we propose a one-year Phase I SBIR project aimed at optimizing our current portfolio of patentable CK1 inhibitors, including compounds with nanomolar potency and excellent brain penetrance, to identify compounds able to significantly block behavioral hyperactivity/stereotypy in the CK1¿OE mouse model, in collaboration with Dr. Flajolet. Upon successful completion of this early discovery/optimization project, we propose to apply for further Phase II SBIR support to investigate the utility of CK1 inhibitors for addressing hyperactivity and other behavioral features of autism in relevant animal models. The overall goal of our program is to (1) identify CK1 inhibitors suitable for development as therapeutic agents and (2) to use these agents to investigate the suitability of CK1 inhibitors for addressing specific behavioral features of the complex, multi-symptom disorder known as autism.

Par-11-133-Pi，Gretchen L.Snyder，博士生酪蛋白激酶I抑制剂用于自闭症 项目摘要/摘要 自闭症是一种神经发育障碍，以不正常的社会互动为特征， 人际交流，以及与许多个体重复的刻板印象行为- 出现相关症状，包括智力障碍、焦虑、癫痫发作、多动症、 对感觉刺激、睡眠障碍和胃肠道的高或低反应 异常现象。值得注意的是，多动、冲动和注意力不集中--注意力的核心特征 缺陷多动障碍(ADHD)-在很高比例(41%-78%)的患者中出现相关症状 自闭症患者。作为一种复杂、多症状的疾病，大量的基因突变(可遗传 和从头开始)以及环境和表观遗传因素可能参与了 自闭症。目前，自闭症还没有治愈或令人满意的治疗方法。新的治疗剂 将有效地解决复杂疾病的具体特征将具有非常重要的意义， 急需之物。酪蛋白激酶1(CK1)是一种与tau相关的蛋白激酶靶标 阿尔茨海默病的神经变性，由昼夜节律决定的睡眠/觉醒周期的中断 时钟，并作为行为多动症的中介物。细胞内治疗公司(ITI)是一个早期阶段 拥有成熟的药物发现平台和发现小分子药物的专业知识的制药公司 蛋白质磷酸二酯酶(PDE1)和蛋白激酶的分子抑制剂，如CK1。我们长久以来 合作者，洛克菲勒大学Paul Greengard博士实验室的Marc Flajolet博士已经 证明了经过改造的小鼠在前脑受限的四环素中过表达CK1 Delta(？) 诱导方式(CK1？OE小鼠)表现出行为多动和刻板行为 让人联想到自闭症和多动症等神经发育障碍。ITI已经确定了有效的和 选择性CK1抑制剂，是代表新化学物质的口服生物可用类药物 实体。在此，我们提出了一个为期一年的第一阶段SBIR项目，旨在优化我们现有的 可申请专利的CK1抑制剂，包括具有纳摩尔效力和出色脑透性的化合物， 识别能够显著阻断CK1？OE中的行为多动/刻板印象的化合物 小鼠模型，与Flajolet博士合作。在成功完成此提早工作后 发现/优化项目，我们建议申请进一步的第二阶段SBIR支持，以研究 CK1抑制剂在改善自闭症患者多动和其他行为特征方面的作用 动物模型。我们计划的总体目标是：(1)确定适合于开发的CK1抑制剂 作为治疗药物和(2)使用这些药物来研究CK1抑制剂对 解决被称为自闭症的复杂、多症状障碍的特定行为特征。