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

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

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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侵略性疾病，由各种遗传异常引起，其特征是存在未分化的血细胞。新兴证据表明急性白血病复发从白血病干细胞（LSC）的活性的结果，对化学疗法有抵抗力需要诱导LSC分化的新药理剂。自我更新和差异化包括LSC在内的干细胞的能力取决于Polycomb抑制复合物的活性1 （PRC1）。所有PRC1复合物的核心包括涉及RING1B或RING1A的异二聚体复合物以及一种PCGF1-6旁系同源物，它催化了组成A组蛋白H2A（H2AUB）的单次化强烈的压抑标记。核心PRC1组件ring1a/b的同时耗竭导致损失 H2AUB沉积，细胞生长停滞和由癌基因驱动的急性白血病细胞的分化与Hoxa9的表达相关。因此，用小分子阻止PRC1活性可能导致消除LSC和白血病爆炸的分化。该项目的主要目标是开发有效的小分子抑制剂，以阻止PRC1的活性直接抑制RING1B-BMI1 E3泛素连接酶诱导白血病细胞的分化。为此，我们采用了基于碎片的筛查，然后进行了广泛的药物化学，以发展第一类直接与RING1A/B蛋白结合并通过阻止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的摄入并诱导白血病细胞和原发性AML样品的分化。该提议的目的是优化这类化合物并使用具有优化的药物样特性的有效PRC1抑制剂并在急性白血病动物模型中发出的体内功效。我们将采用大量药用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确定结合亲和力，抑制活性和细胞活性以抑制H2AUB。最好的化合物将是在白血病细胞系中进行了广泛的评估。我们将评估PRC1的作用机理抑制剂并在LSC的模型和初级AML患者样品中测试其活性。优化化合物将在体内评估，以阻止小鼠模型中白血病发展的潜力 AML。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，可能导致开发高度有价值的化学探针化合物或新型药理学剂急性白血病患者。