Small molecule modulators of ΔFosB

项目摘要 迫切需要制定有效的战略，打击吸毒成瘾这一重大的公共卫生负担。 不幸的是，目前的努力由于侧重于范围非常有限的药物目标而受到阻碍。几十年的工作 已经确定转录因子DFosB在啮齿动物的药物成瘾行为中起关键作用 模型，并在人类中进行验证。对慢性可卡因或阿片类药物（例如，海洛因） 在药物施用中，DFosB介导药物寻求、奖励、自我施用和复发的方面。由于其 由于DFosB具有不寻常的稳定性，它在大脑中对奖励至关重要的区域积累到非常高的水平，使其成为一种 成瘾治疗的诱人目标。然而，DFosB功能的关键机制方面尚不清楚， 使得难以将DFosB作为治疗靶点。目前还不知道DFosB分子如何排列 在体内，什么样的分子特征控制着它们与DNA结合并打开或关闭基因的能力，以及这些分子特征是否 特征可以用小分子策略性地靶向，以便在体内调节DFosB功能， 药物使用障碍我们假设，通过用小分子调节p53 FosB， 调节关键的战略DFosB基因靶点，从而调节长期的神经和行为适应， DFosB触发响应慢性药物使用。为了验证我们的假设，我们建议1）优化一系列 在体外和体内将经验证的先导化合物转化为靶向DFosB的高亲和力化学探针; 2）阐明如何 DFosB中的关键分子特征调节其作用; 3）确定如何靶向这些特征， 我们的化学探针或新的遗传工具改变了成瘾动物模型的行为。为此我们 一个杰出的转化研究团队，负责监督一个强大而有效的实验平台， 我们之前的合作成果我们已经取得了重要的里程碑。首先，我们发现， DFosB不仅与JunD合作，而且与自身合作以结合DNA，这两种物种在结构上是相同的。 在功能上非常不同。第二，我们发现了一个分子开关，控制它的结合 与DNA结合，并且在异聚体与同聚体的cDNAFosB复合物中起不同的作用。第三，我们制定了 大量的靶向DFosB的先导化合物，我们可以利用它们来获得基本的机理 深入了解DFosB功能，以及评估其对成瘾行为的体内作用。我们的工作 创建了一个强大的、以前不可用的、高度可操作的平台，以测试DFosB作为 治疗靶点这项工作的积极影响将是进一步降低DFosB作为治疗靶点的风险， 创造全面的，基于机制的知识，药物发现计划将锚定， 专注于一个全新的目标来对抗成瘾。这一创新提案将提供新的见解 药物成瘾的病理生理学，以及在细胞和动物模型中验证的新型化学探针， 它们一起将作为强有力的平台，从该平台靶向DFosB用于治疗或诊断目的。

PROJECT SUMMARY There is an urgent need to develop effective strategies to combat drug addiction, a major public health burden. Unfortunately, current efforts are hampered by a focus on a very limited range of drug targets. Decades of work have established that the transcription factor DFosB plays a critical role in drug addictive behaviors in rodent models, with validation in humans available as well. In response to chronic cocaine or opioids (e.g., heroin) administration, DFosB mediates aspects of drug seeking, reward, self-administration, and relapse. Due to its unusual stability, DFosB accumulates to very high levels in the brain in regions critical for reward, making it an attractive target for addiction therapies. However, critical mechanistic aspects of DFosB function are not known, making it difficult to pursue DFosB as a therapeutic target. It is not known how DFosB molecules are arranged in vivo, what molecular features control their ability to bind to DNA and turn genes on or off, and whether these features can be targeted strategically with small molecules in order to regulate DFosB function in vivo to combat drug use disorders. We hypothesize that, by modulating ∆FosB with small molecules, we can selectively regulate key strategic DFosB gene targets, and thereby the long-term neural and behavioral adaptations that DFosB triggers in response to chronic drug use. To test our hypotheses, we propose to 1) optimize a series of validated lead compounds into high-affinity chemical probes targeting DFosB in vitro and in vivo; 2) unravel how key molecular features in DFosB regulate its actions; and 3) determine how targeting these features either with our chemical probes or novel genetic tools alters behaviors in animal models of addiction. To this end, we have an outstanding translational research team overseeing a robust and effective experimental platform that draws on our prior combined work. We have already achieved important milestones. First, we have discovered that DFosB partners not only with JunD but also with itself in order to bind DNA, and these two species are structurally and functionally very different. Second, we have uncovered a molecular switch in ∆FosB that controls its binding to DNA and that works differently in heteromeric vs. homomeric ∆FosB complexes. Third, we have developed a large panel of lead compounds that target DFosB and that we can leverage to gain both fundamental mechanistic insight into DFosB function, as well as assess their in vivo effects on addictive behaviors. Together, our work creates a powerful, previously unavailable, and highly actionable platform to test the utility of DFosB as a therapeutic target. The positive impact of this work will be to further de-risk DFosB as a therapeutic target by creating comprehensive, mechanism-based knowledge onto which a drug discovery program will be anchored, focused on a completely novel target to combat addiction. This innovative proposal will provide novel insight into the pathophysiology of drug addiction, and novel chemical probes validated in cells and animal models, which together will serve as a strong platform from which to target DFosB for therapeutic or diagnostic purposes.