Selective HDAC3 Inhibitors as a Novel Therapy for Drug Addiction

选择性 HDAC3 抑制剂作为药物成瘾的新疗法

• 批准号: 9140978
• 负责人: Edward Holson
• 金额: $ 22.5万
• 依托单位: KDAC THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-15 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140978
• 关键词: Abstinence; Acetylation; Address; Animal Model; Atlases; Back; Behavior; Behavioral; Benchmarking; Biological; Brain; Cocaine; Cocaine Dependence; Cognitive Therapy; Combined Modality Therapy; Comorbidity; Complex; Coupled; Data; Development; Disease; Dose; Dose-Limiting; Drug Addiction; Drug abuse; Epigenetic Process; Extinction (Psychology); FDA approved; Fright; Funding; Gene Expression; Gene Targeting; Generations; Genetic; Gold; HDAC1 gene; HDAC11 gene; HDAC3 gene; Histone Deacetylase; Histone Deacetylase Inhibitor; Histones; In Vitro; Individual; Laboratories; Lead; Learning; Legal patent; Licensing; Lysine; Measures; Memory; Methods; Modeling; Mus; Neurobiology; Outcome; Patients; Persons; Pharmaceutical Preparations; Phase; Play; Population; Positioning Attribute; Post-Traumatic Stress Disorders; Property; Protein Isoforms; Public Health; Rattus; Relapse; Reproducibility; Research; Risk; Rodent Model; Seeds; Self Administration; Sodium Butyrate; Substance Use Disorder; Substance abuse problem; Surrogate Markers; Testing; Therapeutic; Therapeutic Index; Time; Toxic effect; Translating; Treatment Efficacy; Triage; Vorinostat; addiction; base; brain research; classical conditioning; cocaine use; design; disorder later incidence prevention; drug abstinence; drug seeking behavior; expectation; improved; in vivo; inhibitor/antagonist; lead series; learning extinction; long term memory; memory process; minimal risk; neurobehavioral; novel; novel therapeutics; phase 1 study; pre-clinical; preference; prevent; public health relevance; reinforced behavior; research clinical testing; response; small molecule therapeutics; success; tool

 DESCRIPTION (provided by applicant): Drug addiction is a serious, and growing, public health problem in the US. Combining medications with cognitive behavioral therapy (CBT) is an effective way for patients to attain and sustain abstinence, yet current safe medications are limited and there are no FDA-approved therapeutics for cocaine addiction, where CBT alone has poor success and relapse rates are high. Histone deacetylase (HDAC) inhibitors such as SAHA (Vorinostat) or sodium butyrate facilitate extinction of drug-seeking in animal models, consistent with the growing understanding of epigenetic mechanisms in learning and memory, and providing proof of concept for such a pharmacotherapeutic approach. The problem is that all FDA-approved and current pre-clinical HDAC inhibitors are (a) not sufficiently isoform selective (inhibiting many of the 11 HDAC isoforms), (b) not safe for non-oncological application (toxicity driven by both HDAC1/2 inhibition and off-target effects), and (c) have poor CNS drug-like properties. Highly isoform-selective HDAC inhibitors are needed to mitigate these risks and increase the therapeutic window. We believe HDAC3 is the best target, as genetic or pharmacological inhibition of HDAC3 persistently enhances long-term memory. Furthermore, blocking HDAC3 pharmacologically or genetically enhances extinction of drug-seeking behavior and blocks reinstatement. Preliminary Data: KDAc Therapeutics is developing novel, highly optimized selective HDAC3 inhibitors and our lead development candidate, KDAC0001, has been extensively characterized in vitro and in vivo. Its preliminary pre-clinical ADME/PK/ toxicological profile, coupled with good CNS drug properties and initial efficacy in learning and memory paradigms, enables its use in definitive proof-of-concept studies in animal models of drug addiction. Hypothesis: We hypothesize that KDAC0001 or other KDAc compounds, when delivered at relatively safe exposure levels, will enhance extinction of drug-seeking behavior in rodent models, revealed as effects on rate of extinction across days and persistence of extinction against reinstatement challenges. Specific Aims: (1) Evaluate KDAC0001 in vivo efficacy and target engagement in two rodent models of addiction; (2) Develop and characterize second generation (2nd gen) novel compounds, focusing on improved HDAC selectivity, potency and CNS drug-like properties; and (3) Evaluate optimal 2nd gen compounds for in vivo efficacy and measure select surrogate markers to correlate behavioral effects with HDAC3 target engagement. This Phase I study will allow us to determine the feasibility of HDAC3 selective inhibition and demonstrate definitive proof of concept in models of drug addiction. Specifically, we aim to establish robust efficacy with an HDAC3-selective KDAc compound, and will define both the necessary compound attributes needed for efficacy and the therapeutic window, and identify a suitable development candidate as co-therapy to prevent relapse of drug addiction.

 描述（由申请人提供）：药物成瘾是美国一个严重的，日益严重的公共卫生问题。将药物与认知行为疗法（CBT）相结合是患者实现和维持戒断的有效方法，但目前安全的药物有限，并且没有FDA批准的可卡因成瘾疗法，其中单独使用CBT的成功率很低，复发率很高。组蛋白脱乙酰酶（HDAC）抑制剂如SAHA（伏立诺他）或丁酸钠促进动物模型中药物寻求的消失，这与对学习和记忆中的表观遗传机制的日益理解一致，并为这种药理学方法提供了概念证明。问题在于，所有FDA批准的和目前的临床前HDAC抑制剂（a）没有足够的同种型选择性（抑制11种HDAC同种型中的许多种），（B）对于非肿瘤学应用不安全（由HDAC 1/2抑制和脱靶效应驱动的毒性），和（c）具有差的CNS药物样性质。需要高度亚型选择性的HDAC抑制剂来减轻这些风险并增加治疗窗口。我们认为HDAC 3是最好的靶点，因为HDAC 3的遗传或药理学抑制持续增强长期记忆。此外，阻断HDAC 3基因或遗传增强了寻求药物行为的消失并阻止了恢复。初步数据：KDAc Therapeutics正在开发新型、高度优化的选择性HDAC 3抑制剂，我们的主要开发候选药物KDAC 0001已在体外和体内进行了广泛的表征。其初步的临床前ADME/PK/毒理学特征，加上良好的CNS药物特性和在学习和记忆模式中的初步疗效，使其能够用于药物成瘾动物模型的明确概念验证研究。假设：我们假设，KDAC 0001或其他KDAc化合物在相对安全的暴露水平下给药时，将增强啮齿动物模型中药物寻求行为的消退，表现为对几天内消退率的影响以及对恢复挑战的消退持续性。具体目标：（1）在两种啮齿动物成瘾模型中评价KDAC 0001的体内疗效和靶点结合;（2）开发和表征第二代（第二代）新型化合物，重点是改善HDAC选择性、效力和CNS药物样特性;（3）评价最佳第二代化合物的体内疗效，并测量选择的替代标志物，以将行为效应与HDAC 3靶点结合相关联。这项I期研究将使我们能够确定HDAC 3选择性抑制的可行性，并在药物成瘾模型中证明明确的概念证明。具体而言，我们的目标是用HDAC 3选择性KDAc化合物建立稳健的疗效，并将定义疗效和治疗窗口所需的必要化合物属性，并确定合适的开发候选物作为共同治疗以防止药物成瘾复发。