Targeting mitochondrial protein synthesis with tigecycline for the treatment of l

描述（由申请人提供）：fda批准的具有先前未被识别的抗白血病活性的药物可以通过利用该化合物先前的毒理学和药理学数据，快速重新定位于该新适应症。为了鉴定对白血病细胞和白血病干细胞具有细胞毒性的药物，我们编制了一个化学文库，其中包含有广泛的治疗窗口和充分了解的药代动力学的药物，重点是抗微生物药物和代谢调节剂。然后我们筛选该文库并鉴定抗菌替加环素。在临床前研究中，替加环素在体外可达到的药理学浓度下诱导白血病细胞系和原发患者样本的细胞死亡。此外，替加环素全身治疗在小鼠模型中延缓了白血病细胞系和原发性AML样本的肿瘤生长。从机制上说，我们的初步数据表明，替加环素通过抑制线粒体蛋白质合成从而破坏线粒体膜电位而起到抗白血病的作用。在本申请中，我们将确定替加环素作为抗白血病药物的作用机制，并验证我们的假设，即它通过抑制线粒体蛋白质合成起作用，抑制氧化磷酸化的破坏，从而激活线粒体途径的半胱天冬酶激活。我们还将定义白血病细胞对氧化磷酸化的生存依赖性，以及白血病细胞系和原代样品中氧化磷酸化途径的能力。在这里，我们假设白血病细胞系、原发性AML细胞和白血病干细胞在呼吸功能受损、耗氧量减少、线粒体膜电位丧失和最终细胞死亡之前，只能容忍呼吸复合体活性的微小降低。因此，我们预测这些差异将解释对替加环素的敏感和不敏感。最后，我们将利用替加环素先前的毒理学和药理学，在复发和难治性AML患者中开展I期临床试验。在本试验的背景下，我们将进行相关研究，并测量血浆和细胞内的替加环素水平。我们还将进行药效学研究，以确定替加环素是否会降低原发性白血病母细胞中线粒体翻译蛋白的表达。因此，通过这项工作，我们将开发一种新的治疗白血病的治疗策略。此外，我们将迅速将实验室的发现转化为临床。值得注意的是，这种药物将是用于治疗恶性肿瘤的一流线粒体蛋白合成抑制剂。

DESCRIPTION (provided by applicant): FDA-approved drugs with previously unrecognized anti-leukemia activity could be rapidly repositioned for this new indication by leveraging the prior toxicology and pharmacology data on the compound. To identify drugs cytotoxic to leukemia cells and leukemia stem cells, we compiled a chemical library of on-patent and off-patent drugs with wide therapeutic windows and well-understood pharmacokinetics focused on anti-microbials and metabolic regulators. We then screened this library and identified the antimicrobial tigecycline. In preclinical studies, tigecycline induced cell death in leukemia cell lines and primary patient samples in vitro at pharmacologically achievable concentrations. Moreover, systemic treatment with tigecycline delayed tumor growth of leukemia cell lines and primary AML samples in mouse models. Mechanistically, our preliminary data suggest that tigecycline acts as an anti-leukemic agent by inhibiting mitochondrial protein synthesis and thereby disrupting mitochondrial membrane potential. In this application, we will determine the mechanism of action of tigecycline as an anti-leukemic agent and test our hypothesis that it acts by inhibiting mitochondrial protein synthesis inhibiting that results in disruption of oxidative phosphorylation, leading to activating the mitochondrial pathway of caspase activation. We will also define the dependence of leukemia cells on the oxidative phosphorylation for survival and the capacity of the oxidative phoshphorylation pathway in leukemia cell lines and primary samples. Here, we hypothesize that leukemia cell lines, primary AML cells, and leukemia stem cells can tolerate only small reductions in the activity of the respiratory complex before there is impairment of respiration, reduced oxygen consumption, loss of mitochondrial membrane potential and ultimately cell death. As such, we predict that these differences will explain sensitivity and insensitivity to tigecycline. Finally, we will leverage the prior toxicology and pharmacology with tigecycline to initiate a phase I clinical trial in patients with relapsed and refractory AML. In the context of this trial, we will conduct correlative studies and measure plasma and intracellular levels of tigecycline. We will also conduct pharmacodynamic studies to determine whether tigecycline decreases the expression of mitochondrially translated proteins in the primary leukemic blasts. Thus, through this work, we will develop a novel therapeutic strategy for the treatment of leukemia. In addition, we will rapidly translate findings from our lab to the clinic. Of note, this drug would be a first-in-class mitochondrial protein synthesis inhibitor used for the treatment of malignancy.