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 急性白血病是由各种遗传异常引起的侵袭性疾病，其特征在于： 未分化的血细胞的存在。新的证据表明，急性白血病复发 结果来自白血病干细胞（LSC）的活性，LSC对化疗具有抗性，支持了 需要诱导LSC分化的新药理学试剂。自我更新和分化 包括LSC在内的干细胞的能力依赖于Polycomb抑制复合物1的活性 （PRC 1）。所有PRC 1复合物的核心包括涉及RING 1B或RING 1A的异二聚体复合物 和PCGF 1 -6旁系同源物之一，其催化组蛋白H2 A（H2 Aub）的单泛素化，构成一个 强烈压抑的印记。堆芯PRC 1组件RING 1A/B的同时耗尽导致 癌基因驱动的急性白血病细胞H2 Aub沉积、细胞生长停滞和分化 与HOXA 9的表达相关。因此，用小分子阻断PRC 1活性可能导致 根除LSC和分化白血病母细胞。 该项目的主要目标是开发有效的小分子抑制剂，通过抑制PRC 1的活性， 直接抑制RING 1B-BMI 1 E3泛素连接酶以诱导白血病细胞分化。为此目的， 我们采用基于片段的筛选，然后进行广泛的药物化学研究， 直接结合RING 1A/B蛋白并通过阻断PRC 1活性的小分子， PRC 1复合物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 并诱导白血病细胞和原发性AML样品的分化。这项提案的目的是 以优化这类化合物并开发具有优化药物样特性的有效PRC 1抑制剂 并且在急性白血病的动物模型中具有显著的体内功效。我们将使用大量的药物 基于化学和结构的设计方法来优化PRC 1抑制剂。将对所有抑制剂进行表征 以测定结合亲和力、抑制活性和抑制H2 Aub的细胞活性。最好的化合物是 在一组白血病细胞系中进行了广泛的评估。我们将评估中华人民共和国的作用机制1 抑制剂，并在LSC模型和原发性AML患者样品中测试其活性。优化 化合物将在体内评估它们阻断小鼠白血病模型中白血病发展的潜力。 急性髓细胞白血病我们的研究将探索诱导白血病细胞和LSC分化的新方法， 导致开发高度有价值的化学探针化合物或新的药理学试剂， 急性白血病患者。