Targeting PRC1 in leukemia

靶向 PRC1 治疗白血病

基本信息

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
项目类别：
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

项目摘要

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.

抽象的急性白血病是一种由多种基因异常引起的侵袭性疾病，其特征是未分化血细胞的存在。新的证据表明急性白血病复发这是白血病干细胞 (LSC) 活性的结果，它对化疗有抵抗力，支持需要新的药物来诱导 LSC 分化。自我更新和分化干细胞（包括 LSC）的能力取决于 Polycomb 抑制复合物 1 的活性（中国1）。所有 PRC1 复合物的核心均包含涉及 RING1B 或 RING1A 的异二聚体复合物和 PCGF1-6 旁系同源物之一，催化组蛋白 H2A (H2Aub) 的单泛素化，构成强烈的压制印记。核心 PRC1 组件 RING1A/B 的同时耗尽会导致癌基因驱动的急性白血病细胞H2Aub沉积、细胞生长停滞和分化与 HOXA9 的表达相关。因此，用小分子阻断 PRC1 活性可能会导致根除 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 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，我们采用基于片段的筛选，然后进行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 PRC1 活性来抑制 PRC1 活性的小分子 PRC1 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 H2Aub 并诱导白血病细胞和原发性 AML 样本的分化。该提案的目标是优化此类化合物并开发具有优化类药特性的有效 PRC1 抑制剂在急性白血病动物模型中具有显着的体内疗效。我们将采用广泛的药物基于化学和结构的设计方法来优化 PRC1 抑制剂。所有抑制剂都将被表征以确定抑制 H2Aub 的结合亲和力、抑制活性和细胞活性。最好的化合物将是在一组白血病细胞系中进行了广泛评估。我们将评估 PRC1 的作用机制抑制剂并在 LSC 模型和原发性 AML 患者样本中测试其活性。优化后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反洗钱。我们的研究将探索一种诱导白血病细胞和LSC分化的新方法，并可能导致开发高价值的化学探针化合物或新型药物制剂急性白血病患者。