Targeting mitochondrial protein synthesis with tigecycline for the treatment of l

描述（由申请人提供）：通过利用该化合物的既往毒理学和药理学数据，FDA批准的具有先前未识别的抗白血病活性的药物可以快速重新定位用于这种新适应症。为了鉴定对白血病细胞和白血病干细胞有细胞毒性的药物，我们编制了一个专利和非专利药物的化学库，这些药物具有广泛的治疗窗口和充分理解的药代动力学，重点是抗微生物和代谢调节剂。然后，我们筛选了该文库并鉴定了抗微生物剂替加环素。在临床前研究中，替加环素在体外可达到的浓度下诱导白血病细胞系和原代患者样本中的细胞死亡。此外，在小鼠模型中，用替加环素全身治疗延迟白血病细胞系和原发性AML样品的肿瘤生长。从机制上讲，我们的初步数据表明，替加环素作为一种抗白血病药物，通过抑制线粒体蛋白质合成，从而破坏线粒体膜电位。 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合成，抑制导致氧化磷酸化破坏，从而激活caspase激活的线粒体途径发挥作用。 我们还将确定白血病细胞生存对氧化磷酸化的依赖性以及白血病细胞系和原始样本中氧化磷酸化途径的能力。在此，我们假设白血病细胞系、原代AML细胞和白血病干细胞在呼吸受损、耗氧量降低、线粒体膜电位丧失和最终细胞死亡之前只能耐受呼吸复合物活性的小幅降低。因此，我们预测这些差异将解释对替加环素的敏感性和不敏感性。 最后，我们将利用替加环素先前的毒理学和药理学，在复发性和难治性AML患者中启动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替加环素的血浆和细胞内水平。我们还将进行药效学研究，以确定替加环素是否降低原发性白血病原始细胞中的翻译蛋白的表达。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，我们将迅速将研究结果从实验室转化为临床。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.