Targeting DOT1L for Degradation in MLL-rearranged Leukemia

靶向 DOT1L 降解 MLL 重排白血病

• 批准号: 10411945
• 负责人: SCOTT A ARMSTRONG
• 金额: $ 39.6万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411945
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute leukemia; Address; Adult; Apoptotic; Area; Automobile Driving; Binding; Biological; Biological Assay; Biological Models; Biology; Cell Culture Techniques; Cell Line; Cell model; Cells; Chemicals; Chemistry; Child; Childhood; Childhood Leukemia; Chimeric Proteins; Chromatin Structure; Chromosomal translocation; Clinic; Clinical; Clinical Trials; Communities; Continuous Intravenous Infusion; Coupled; Dependence; Development; Diagnosis; Disease; Dose; Drug Design; Drug resistance; Effectiveness; Enzymes; Epigenetic Process; Foundations; Funding; Gene Expression; Generations; Genes; Genetic; Genetic study; Grant; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Histones; Homeobox; Human; Hypermethylation; In Vitro; Joints; Knowledge; Laboratories; Lead; Leukemic Cell; Link; Lysine; MLL gene; MLL-AF9; MLL-rearranged leukemia; Maintenance; Malignant Neoplasms; Medical; Methylation; Methyltransferase; Modeling; Mus; NPM1 gene; Oncogenic; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phase I Clinical Trials; Play; Prognosis; Protein Engineering; Proteins; Publications; Qi; Reagent; Refractory; Relapse; Reporting; Research; Resistance; Resistance development; Role; Signal Transduction; System; Testing; Therapeutic; Therapeutic Trials; Translations; Work; acute myeloid leukemia cell; base; chemical genetics; chemotherapy; chromatin modification; clinical candidate; clinical investigation; combinatorial; drug action; drug discovery; epigenomics; experience; gene translocation; genetic approach; genome-wide; histone methyltransferase; human model; in vivo; inhibitor; inhibitor therapy; insight; lead optimization; leukemia; leukemogenesis; member; mutant; novel; novel therapeutics; patient derived xenograft model; pre-clinical; preclinical study; prevent; programs; protein degradation; protein function; recruit; resistance mechanism; response; scaffold; small molecule; small molecule inhibitor; stem cells; success; targeted treatment; tool; translational model; tumor progression; ubiquitin-protein ligase

Project Summary/Abstract Despite marked progress in the rate of cure among patients with acute leukemia, chromosomal translocations involving the mixed lineage leukemia gene (MLL1) give rise to highly aggressive acute leukemias associated with poor clinical outcomes for pediatric and adult patients. Current treatment options are of limited effectiveness; thus, there is a pressing need for new therapies for this disease. Genetic studies have demonstrated that the histone methyltransferase DOT1L is required for the development and maintenance of MLL-rearranged (MLL-r) leukemia in model systems. Likewise, work from the previous funding cycle clearly defined a role for DOT1L inhibition in MLL-r leukemia through characterization of a potent, specific DOT1L inhibitor, EPZ-5676 (pinometostat), that has remarkably selective anti-proliferative and pro-apoptotic effects on MLL-rearranged cells. As pinometostat has progressed through Phase I clinical trials, responses and subsequent relapses imply the development of acquired resistance to the inhibitor. In this proposal, we seek to understand the biological underpinnings of DOT1L inhibitor resistance and develop a novel class of small molecule DOT1L degraders to overcome resistance. In Specific Aim 1, we seek to understand the mechanisms of resistance through detailed studies of chromatin structure and gene expression following the development of acquired resistance to DOT1L inhibitor therapy. We will also investigate the non-enzymatic role of DOT1L in MLL-r leukemia and define dependencies acquired in the resistant state. In Specific Aim 2, we will lead a chemistry and chemical biology campaign and develop an assay platform for the identification and optimization of the first small molecule degraders of endogenous DOT1L protein. In Specific Aim 3, we will utilize our cell culture and patient-derived xenograft models of MLL-r leukemia to explore the impact of DOT1L degradation on gene expression and tumor progression while driving hit-to-lead optimization of DOT1L degraders that can prompt clinical investigation. We will also test pharmacological hypotheses regarding combinatorial drug action with DOT1L degraders in predictive human models of MLL-r leukemia. We expect these aims to bring new more efficacious, less toxic therapies to children and adults diagnosed with this devastating disease.

项目总结/摘要 尽管在急性白血病患者的治愈率方面取得了显著进展，但染色体易位仍是一个重要的问题。 涉及混合谱系白血病基因（MLL 1）的急性白血病， 儿科和成人患者的临床结果较差。目前的治疗方案效果有限; 因此迫切需要新的治疗方法。遗传学研究表明， 组蛋白甲基转移酶DOT 1 L是MLL-r的发展和维持所必需的。 白血病模型系统同样，上一个资助周期的工作明确界定了DOT 1 L的作用 一种有效特异性DOT 1 L抑制剂EPZ-5676对MLL-r白血病的抑制作用 （pinometostat），其对MLL重排的细胞具有显著的选择性抗增殖和促凋亡作用。 细胞随着pinometostat在I期临床试验中的进展，缓解和随后的复发意味着 对抑制剂产生获得性耐药性。在这个建议中，我们试图了解生物学 DOT 1 L抑制剂抗性的基础，并开发一类新的小分子DOT 1 L降解剂， 克服阻力。在具体目标1中，我们试图通过详细的方法来了解耐药机制。 对DOT 1 L获得性耐药发展后的染色质结构和基因表达的研究 抑制剂疗法我们还将研究DOT 1 L在MLL-r白血病中的非酶促作用， 在抵抗状态下获得的依赖性。在具体目标2中，我们将带领化学和化学生物学 活动并开发用于鉴定和优化第一个小分子的测定平台 内源性DOT 1 L蛋白的降解剂。在具体目标3中，我们将利用我们的细胞培养和患者来源的 MLL-r白血病异种移植模型，以探索DOT 1 L降解对基因表达和肿瘤的影响 在推动DOT 1 L降解剂的点击到铅优化的同时，可以促进临床研究。我们 还将测试关于DOT 1 L降解剂组合药物作用的药理学假设， MLL-r白血病的预测性人类模型。我们希望这些目标能带来新的更有效，毒性更小的 为被诊断患有这种毁灭性疾病的儿童和成人提供治疗。

项目成果

A Bead-Based Proximity Assay for BRD4 Ligand Discovery.

• DOI: 10.1002/9780470559277.ch150024
• 发表时间: 2015-12-02
• 期刊: Current protocols in chemical biology
• 作者: Roberts JM;Bradner JE
• 通讯作者: Bradner JE

AF10 regulates progressive H3K79 methylation and HOX gene expression in diverse AML subtypes.

• DOI: 10.1016/j.ccell.2014.10.009
• 发表时间: 2014-12-08
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Deshpande AJ;Deshpande A;Sinha AU;Chen L;Chang J;Cihan A;Fazio M;Chen CW;Zhu N;Koche R;Dzhekieva L;Ibáñez G;Dias S;Banka D;Krivtsov A;Luo M;Roeder RG;Bradner JE;Bernt KM;Armstrong SA
• 通讯作者: Armstrong SA

Transcription control by the ENL YEATS domain in acute leukaemia.

• DOI: 10.1038/nature21688
• 发表时间: 2017-03-09
• 期刊: Nature
• 影响因子: 64.8
• 作者: Erb MA;Scott TG;Li BE;Xie H;Paulk J;Seo HS;Souza A;Roberts JM;Dastjerdi S;Buckley DL;Sanjana NE;Shalem O;Nabet B;Zeid R;Offei-Addo NK;Dhe-Paganon S;Zhang F;Orkin SH;Winter GE;Bradner JE
• 通讯作者: Bradner JE

Genomic dark matter sheds light on EVI1-driven leukemia.

基因组暗物质揭示了 EVI1 驱动的白血病。

• DOI: 10.1016/j.ccr.2014.03.031
• 发表时间: 2014
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Koche,RichardP;Armstrong,ScottA
• 通讯作者: Armstrong,ScottA

BET Bromodomain Proteins Function as Master Transcription Elongation Factors Independent of CDK9 Recruitment.

• DOI: 10.1016/j.molcel.2017.06.004
• 发表时间: 2017-07-06
• 期刊: Molecular cell
• 影响因子: 16
• 作者: Winter GE;Mayer A;Buckley DL;Erb MA;Roderick JE;Vittori S;Reyes JM;di Iulio J;Souza A;Ott CJ;Roberts JM;Zeid R;Scott TG;Paulk J;Lachance K;Olson CM;Dastjerdi S;Bauer S;Lin CY;Gray NS;Kelliher MA;Churchman LS;Bradner JE
• 通讯作者: Bradner JE