Small molecule modulators of ΔFosB

项目总结 迫切需要制定有效的战略来打击吸毒成瘾，这是一种主要的公共卫生负担。 不幸的是，目前的努力由于集中在非常有限的药物靶标上而受到阻碍。几十年的工作 已经证实转录因子DFosB在啮齿动物的药物成瘾行为中起关键作用 模型，也可以在人类身上进行验证。对慢性可卡因或阿片类药物(如海洛因)的反应 在药物管理方面，DFosB调节药物寻求、奖励、自我管理和复发。由于其 不同寻常的稳定性，DFosB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 成瘾疗法有吸引力的靶子。然而，DFosB函数的关键机械方面是未知的， 这使得将DFosB作为治疗靶点变得困难。目前尚不清楚DFosB分子是如何排列的 在活体中，什么分子特征控制它们与DNA结合并开启或关闭基因的能力，以及这些 可以有策略地靶向功能小分子，以调节DFosB在体内的功能来对抗 药物使用障碍。我们假设，通过用小分子调制∆FosB，我们可以选择性地 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是对慢性药物使用的反应。为了检验我们的假设，我们建议1)优化一系列 在体外和体内将经过验证的先导化合物转化为针对DFosB的高亲和力化学探针；2)揭示 DFosB中的关键分子特征调节其行为；以及3)决定如何通过以下两种方式来靶向这些特征 我们的化学探针或新的遗传工具改变了上瘾动物模型的行为。为此，我们有 一个优秀的翻译研究团队，监督一个强大而有效的实验平台， 关于我们之前的联合工作。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，还与自己合作，以结合DNA，这两个物种在结构上是 在功能上也截然不同。其次，我们在∆FosB中发现了一个控制其结合的分子开关 这在异构体和均聚体∆FosB复合体中的作用不同。第三，我们开发了一种 以DFosB为目标的大量先导化合物面板，我们可以利用它们来获得基本的机制 深入了解DFosB的功能，以及评估它们在体内对成瘾行为的影响。共同努力，我们的工作 创建一个功能强大、以前不可用且高度可操作的平台，以测试DFosB作为 治疗靶点。这项工作的积极影响将是通过以下方式进一步降低DFosB作为治疗目标的风险 创造全面的、基于机制的知识，药物发现计划将以此为基础； 专注于一个全新的打击成瘾的目标。这一创新的建议将提供新的见解 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， 它们共同将成为一个强大的平台，从这里靶向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.