Targeting PRC1 in leukemia

靶向 PRC1 治疗白血病

• 批准号: 10712963
• 负责人: Tomasz Cierpicki
• 金额: $ 62.5万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10712963
• 关键词: Acute Myelocytic Leukemia; Acute leukemia; Affinity; Animal Model; BMI1 gene; Binding; Biology; Blood Cells; Bone Marrow Cells; Cell Line; Cells; Chemicals; Chromatin; Complex; Deposition; Development; Disease; Drug Kinetics; Epigenetic Process; Generations; Goals; HOXA9 gene; Hematopoiesis; Histone H2A; Hydrolysis; Leukemic Cell; Maintenance; Modeling; Molecular Abnormality; Monoubiquitination; Mus; Names; Nucleosomes; Oncogenes; Outcome; PRC1 Protein; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Prodrugs; Property; Proteins; Recurrence; Research; Resistance; Sampling; Solubility; Stem Cell Research; Structure; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Ubiquitination; Undifferentiated; Work; Xenograft Model; acute leukemia cell; acute myeloid leukemia cell; analog; anti-cancer therapeutic; antileukemic agent; cell growth; chemotherapy; clinical application; design; efficacy study; improved; in vivo; inhibitor; innovation; interdisciplinary approach; leukemia; leukemic stem cell; leukemogenesis; mouse model; novel; novel anticancer drug; novel strategies; novel therapeutic intervention; overexpression; paralogous gene; patient derived xenograft model; pharmacologic; screening; self-renewal; small molecule; small molecule inhibitor; stem cells; structural biology; targeted treatment; ubiquitin-protein ligase

Abstract Acute leukemia is an aggressive disease resulting from various genetic abnormalities and is characterized by the presence of undifferentiated blood cells. Emerging evidence shows that recurrence of acute leukemia results from the activity of leukemic stem cells (LSCs), which are resistant to chemotherapy, supporting the need for new pharmacological agents inducing differentiation of LSCs. The self-renewal and differentiation capacity of stem cells, including LSCs, are dependent on the activity of the Polycomb repressive complex 1 (PRC1). The core of all PRC1 complexes comprises heterodimeric complexes involving RING1B or RING1A and one of the PCGF1-6 paralogs, which catalyze monubiquitination of histone H2A (H2Aub) constituting a strong repressive mark. Simultaneous depletion of core PRC1 components RING1A/B results in a loss of H2Aub deposition, cell growth arrest and differentiation of acute leukemia cells driven by the oncogenes associated with expression of HOXA9. Therefore, blocking PRC1 activity with small molecules could lead to eradication of LSCs and differentiation of leukemic blasts. The major goal of this project is to develop potent small molecule inhibitors blocking the activity of PRC1 by a direct inhibition of the RING1B-BMI1 E3 ubiquitin ligase to induce differentiation of leukemic cells. To this end, we employed fragment-based screening followed by extensive medicinal chemistry to develop the first-in-class small molecules that directly bind to the RING1A/B proteins and inhibit PRC1 activity through blocking the interaction of the PRC1 complex with nucleosomes. Our first-generation inhibitor RB-3 decreases global level of H2Aub and induces differentiation in leukemia cells and primary AML samples. The goal of this proposal is to optimize this class of compounds and develop potent PRC1 inhibitors with optimized drug-like properties and pronounced in vivo efficacy in animal models of acute leukemia. We will employ extensive medicinal chemistry and structure-based design approach to optimize PRC1 inhibitors. All inhibitors will be characterized to determine binding affinity, inhibitory activity, and cellular activity to inhibit H2Aub. Best compounds will be extensively evaluated in a panel of leukemia cell lines. We will assess the mechanism of action of the PRC1 inhibitors and test their activity in the models of LSCs and in the primary AML patient samples. The optimized compounds will be assessed in vivo for their potential to block development of leukemia in mouse models of AML. Our studies will explore a new approach to induce differentiation of leukemia cells and LSCs and may lead to the development of highly valuable chemical probe compounds or novel pharmacologic agents for acute leukemia patients.

摘要 急性白血病是一种由各种基因异常引起的侵袭性疾病，其特点是 存在未分化的血细胞。越来越多的证据表明，急性白血病复发 从白血病干细胞(LSCs)的活性来看，这种细胞对化疗具有抗药性，支持 需要新的药物诱导LSCs分化。自我更新与差异化 干细胞的能力，包括LSCs，取决于多梳抑制复合体1的活性 (PRC1)。所有PrC1络合物的核心都是含有Ring1b或Ring1a的异二聚体络合物 和PCGF1-6类似物之一，它催化组蛋白H_2A(H_2Aub)的单泛素化，构成 强烈的压抑痕迹。核心PRC1组件RING1A/B的同时耗尽导致损失 癌基因对急性白血病细胞H_2Aub沉积、细胞生长停滞和分化的影响 与HOXA9的表达相关。因此，用小分子阻断Prc1活性可能导致 LSCs的根除和白血病原始细胞的分化。 该项目的主要目标是开发有效的小分子抑制剂，通过一种有效的方法阻断Prc1的活性。 直接抑制Ring1b-BMI1 E3泛素连接酶诱导白血病细胞分化。为此， 我们使用了基于片段的筛选和广泛的药物化学来开发一流的 直接与RING1A/B蛋白结合并通过阻断RING1A/B蛋白抑制PRC1活性的小分子 Prc1复合体与核小体的相互作用。我们的第一代抑制剂RB-3降低了全球水平 并在白血病细胞和原代AML样本中诱导分化。这项提议的目标是 优化这类化合物并开发具有优化类药物性能的有效PRC1抑制剂 并在急性白血病动物模型中表现出显著的体内疗效。我们将广泛使用医疗设备 基于化学和结构的设计方法来优化Prc1抑制剂。所有的抑制剂都将被表征 测定结合亲和力、抑制活性和细胞活性以抑制H_2Aub。最好的化合物将是 在一组白血病细胞系中进行了广泛的评估。我们将评估革命制度改革委员会的行动机制。 并在LSCs模型和原发AML患者样本中测试它们的活性。经过优化的 将在体内评估化合物在小鼠模型中阻止白血病发展的潜力。 AML。我们的研究将探索一种新的方法来诱导白血病细胞和LSCs分化，并可能 导致开发高价值的化学探针化合物或新的药理试剂 急性白血病患者。