Adenosine Analogs: Therapeutics for Hematologic Cancers

描述(申请人提供)：多发性骨髓瘤和慢性淋巴细胞白血病由无复制或缓慢复制的静止细胞群组成。因此，不以复制DNA为目标的治疗方法，而是专注于转录、翻译、细胞生物能量产生和关键分子途径的治疗方法可能被证明更有效。我们之前已经开发了一种卤化三磷酸腺苷类似物，8-氯腺苷(8-CI-ADO)，它具有独特的RNA导向的作用机制。这种药物的特殊性质，两次成功的RAID奖，以及GMP材料的可获得性，导致了针对血液系统恶性肿瘤患者的临床试验。8-CI-ADO的成功刺激了我们对相关类似物的研究。我们鉴定了8-氨基腺苷(8-NH2-ADO)和8-叠氮腺苷(8-N3-ADO)与8-CI-ADO卤代同系物具有相似的RNA导向作用。在初步研究中，我们已经证明了8-NH2-ADO比卤代同系物更有效和更快的作用。最令人印象深刻的是，8-NH2-ADO导致8-NH2-ATP的大量积累，并伴随着内源性ATP库的减少。此外，RNA合成显著减少，DNA合成也随之减少。在这项拨款提案中，我们将重点关注8-NH2-ADO和8-N3-ADO的独特性质，以推动这些药物进入临床环境。在本提案的目标I中，我们将表征这些药物的代谢，剖析它们对线粒体I功能和随后的细胞生物能量消耗的影响，并探索这些变化如何作用于核酸合成。在AIM II中，我们将通过检测转录和多聚腺苷的变化来进一步剖析对RNA的抑制作用。最后，在目标III中，我们将继续新的观察，即关键信号通路的磷酸化减少及其对细胞凋亡的影响。了解8-修饰的腺苷类似物潜在的作用机制将允许进一步合理的药物设计，并导致识别可能在治疗环境中补充这些药物活性的化合物。与公共卫生的相关性：这些研究建议调查新疗法的作用机制，这些疗法可能有效地治疗目前无法治愈的多发性骨髓瘤和慢性淋巴细胞白血病等缓慢增殖的血液癌症。

DESCRIPTION (provided by applicant): Multiple myeloma and chronic lymphocytic leukemia are composed of non- or slowly- replicating quiescent cell populations. Therefore, therapeutic approaches that do not target replicating DNA, but rather focus on transcription, translation, cellular bioenergy production, and critical molecular pathways may prove to be more effective. We have previously developed a halogenated ATP analog, 8-chloro-adenosine (8-CI-Ado) that has a unique RNA-directed mechanism of action. The special properties of this agent, two successful RAID awards, and availability of the GMP material has resulted in a clinical trial targeting patients with hematologic malignancies. The success of 8-CI-Ado stimulated our investigation of related analogs. We identified 8-amino-adenosine (8-NH2-Ado) and 8-azido-adenosine (8-N3-Ado) in this screen as having similar RNA-directed actions as the 8-CI-Ado halogenated congener. In preliminary studies, we have shown that 8-NH2-Ado actions are more potent and rapid than the halogenated congener. Most impressively, 8- NH2-Ado causes a massive accumulation of 8-NH2-ATP with a concomitant decrease in the endogenous ATP pools. In addition, there is a striking decrease in RNA synthesis, which is followed by a concurrent decrease in DNA synthesis. In this grant proposal, we will focus on the unique properties of 8-NH2-Ado and 8-N3-Ado in order to move these drugs forward to the clinical setting. In Aim I of this proposal, we will characterize the metabolism of these drugs, dissect their effects on mitochondria I function and the subsequent depletion of cellular bioenergy, and explore how these alterations may act on nucleic acid synthesis. In Aim II, we will further dissect the inhibitory actions toward RNA by examining changes in transcription and poly-adenylation. Finally, in Aim III, we will pursue the novel observation of decreased phosphorylation of key signaling pathways and how that impacts on apoptosis. Understanding the mechanisms underlying the actions of 8-modified adenosine analogs will allow for further rational drug design and lead to an identification of compounds that may complement the activity of these drugs in a therapeutic setting. Relevance to public health: These studies propose to investigate the mechanism of action of novel therapeutics that may be effective in treating slowly proliferating cancers of the blood such as multiple myeloma and chronic lymphocytic leukemia; cancers which are currently incurable.