Adenosine Analogs: Therapeutics for Hematologic Cancers

描述（由申请人提供）：多发性骨髓瘤和慢性淋巴细胞白血病由非复制或缓慢复制的静止细胞群组成。因此，不针对复制DNA，而是专注于转录，翻译，细胞生物能生产和关键分子途径的治疗方法可能会被证明更有效。我们以前已经开发了一种卤代ATP类似物，8-氯腺苷（8-CI-Ado），具有独特的RNA导向作用机制。这种药物的特殊性质，两次成功的RAID奖项，以及GMP材料的可用性，导致了针对血液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。我们在该筛选中鉴定出8-氨基-腺苷（8-NH 2-Ado）和8-叠氮基-腺苷（8-N3-Ado）具有与8-Cl-Ado卤化同源物相似的RNA导向作用。在初步研究中，我们已经表明，8-NH 2-Ado的行动是更有力和更迅速的卤代同源物。最令人印象深刻的是，8-NH 2-Ado导致8-NH 2-ATP的大量积累，伴随着内源性ATP库的减少。此外，RNA合成显著减少，随后是DNA合成的同时减少。在这项资助提案中，我们将专注于8-NH 2-Ado和8-N3-Ado的独特性质，以便将这些药物推向临床环境。在本提案的目的I中，我们将描述这些药物的代谢特征，剖析它们对线粒体I功能的影响以及随后的细胞生物能量消耗，并探索这些改变如何影响核酸合成。在目的II中，我们将通过检查转录和多聚腺苷酸化的变化来进一步剖析对RNA的抑制作用。最后，在目标III中，我们将继续对关键信号通路磷酸化水平降低的新观察，以及这对细胞凋亡的影响。了解8-修饰的腺苷类似物的作用机制将允许进一步合理的药物设计，并导致在治疗环境中可以补充这些药物活性的化合物的鉴定。与公共卫生的相关性：这些研究旨在研究新疗法的作用机制，这些新疗法可能有效治疗缓慢增殖的血液癌症，如多发性骨髓瘤和慢性淋巴细胞白血病;目前无法治愈的癌症。

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.