Chemical manipulation of creatine kinases to treat acute myeloid leukemia

肌酸激酶的化学​​操作治疗急性髓系白血病

• 批准号: 10198222
• 负责人: Edward Thomas Chouchani
• 金额: $ 45.07万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10198222
• 关键词: Active Sites; Acute Myelocytic Leukemia; Binding; CSF2 gene; Cell Death; Cell Line; Cell model; Chemicals; Creatine Kinase; Cysteine; Data; Dependence; Development; Disease; Drug Targeting; EVI1 gene; Enzymes; Family; Goals; Growth; Human; Kinetics; Lead; Libraries; Luciferases; Malignant Neoplasms; Metabolic; Metabolism; Modality; Modeling; Modification; Monitor; Mus; Neoplasm Metastasis; Oncogenic; Output; Patients; Pharmaceutical Preparations; Pharmacology; Play; Positioning Attribute; Proteins; Proteome; Rapid screening; Role; Series; Structure; Testing; Tissues; Toxic effect; Treatment Efficacy; Xenograft Model; acute myeloid leukemia cell; cancer cell; clinical application; clinically relevant; cytotoxic; cytotoxicity; improved; in vivo; in vivo Model; inhibitor/antagonist; kinase inhibitor; leukemia; molecular modeling; mouse model; nanomolar; novel; novel strategies; scaffold; screening; small molecule; therapeutically effective

PROJECT SUMMARY: Over the last decade, essential metabolic dependencies of many cancers have been revealed. These dependencies have highlighted that certain nodes of metabolism are attractive drug targets to drive cancer cell death. For the most part, oncogenic metabolic proteins have not been drugged, and many lack obvious binding pockets for pharmacological manipulation. Among the most prominent examples of un-drugged metabolic cancer targets are creatine kinases (CKs). CKs are essential for growth and metastasis of numerous cancers, especially aggressive acute myeloid leukemias (AML). The essentiality of CKs for aggressive AMLs is distinct, as somatic tissues do not rely on CKs for viability. However, despite being a highly actionable drug target in AML, no potent inhibitors exist against CKs. We recently developed a mass spectrometric (MS) platform that allows for rapid screening of small molecules for covalent engagement with protein cysteines across the proteome. With preliminary data, we have combined this platform with a small molecule screening library to systematically identify drug leads targeting cysteines on un-drugged proteins. In doing so, we have identified a lead scaffold that is potently inhibitory against the CK family of enzymes, by selectively targeting a key active site cysteine residue. Moreover, at high nanomolar concentrations, this CK inhibitor is selectively cytotoxic to AML cancers that depend on CKs. The goal of this project is to develop this new scaffold class of CK inhibitor for clinical application in AML cancers. We will test the hypothesis that rational development of this scaffold will improve potency and AML toxicity by targeting key interactions at the CK active site pocket. Moreover, we will determine whether this new CK inhibitor class is an effective therapeutic in a mouse model of AML in vivo. In Aim 1 we will combine molecular modeling approaches and our preliminary SAR data to rationally develop a series of molecules to systematically probe inhibitory potency against the CK active site pocket. Activity and selectivity of these molecules will be determined using our MS platform, isolated CK kinetics, and cellular AML models. In parallel, using patient-derived cellular models of AML, for which CK is essential, we will determine clinically relevant disease-modifying outputs, including viability, colony forming, and on-target toxicity. In Aim 2 we will determine therapeutic efficacy of our CK inhibitor chemotype in mouse models EVI1-positive AML that rely essentially on CKs. Taken together, this project will advance a first-in-class inhibitor of CKs, which is an un-drugged metabolic dependency of AML cancers. Successful completion of these Aims would position this new chemotype for treatment of AML, and provide a new chemical probe for understanding the role CKs play in AML and cellular metabolism.

项目概要： 在过去的十年中，许多癌症的基本代谢依赖性已被揭示。这些 依赖性强调，某些代谢节点是驱动癌症的有吸引力的药物靶点 细胞死亡。在大多数情况下，致癌代谢蛋白尚未被药物化，并且许多缺乏明显的 用于药理操作的结合口袋。不吸毒的最突出的例子之一 代谢性癌症的靶标是肌酸激酶 (CK)。 CK对于肿瘤的生长和转移至关重要 许多癌症，尤其是侵袭性急性髓性白血病 (AML)。 CK 的重要性 侵袭性 AML 是独特的，因为体细胞组织不依赖 CK 来维持活力。然而，尽管是一个 AML 中高度可行的药物靶点，但不存在针对 CK 的有效抑制剂。 我们最近开发了一个质谱 (MS) 平台，可以快速筛选小分子物质 与蛋白质组中的蛋白质半胱氨酸共价结合的分子。有了初步数据，我们 将该平台与小分子筛选库结合起来，系统地识别先导药物 将半胱氨酸靶向未加药的蛋白质。在此过程中，我们发现了一种有效的先导支架 通过选择性地靶向关键活性位点半胱氨酸残基来抑制 CK 家族酶。 此外，在高纳摩尔浓度下，这种 CK 抑制剂对 AML 癌症具有选择性细胞毒性， 取决于 CK。该项目的目标是开发这种新型支架类别的 CK 抑制剂，用于临床 在 AML 癌症中的应用。我们将检验这个支架的合理开发将改善这一假设 通过针对 CK 活性位点口袋的关键相互作用来发挥效力和 AML 毒性。此外，我们将 确定这种新的 CK 抑制剂类是否能有效治疗 AML 小鼠体内模型。 在目标 1 中，我们将结合分子建模方法和我们的初步 SAR 数据来合理开发 一系列分子来系统地探测针对 CK 活性位点口袋的抑制效力。活动 这些分子的选择性将使用我们的 MS 平台、分离的 CK 动力学和 细胞 AML 模型。同时，使用源自患者的 AML 细胞模型（其中 CK 至关重要），我们 将确定临床相关的疾病修饰输出，包括活力、集落形成和目标 毒性。在目标 2 中，我们将确定我们的 CK 抑制剂化学型在小鼠模型中的治疗效果 主要依赖 CK 的 EVI1 阳性 AML。总而言之，该项目将推进一流的 CK 抑制剂，CK 是 AML 癌症的非药物代谢依赖性。顺利完成 这些目标将定位这种新的化学型用于治疗 AML，并为治疗 AML 提供新的化学探针 了解 CK 在 AML 和细胞代谢中的作用。