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Targeting NSD1 in leukemia

靶向白血病中的 NSD1

基本信息

批准号：
10297841
负责人：
Tomasz Cierpicki
金额：
$ 44.21万
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：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10297841
关键词：
Acute Myelocytic Leukemia Acute leukemia Affect Alkynes Allosteric Site Animal Model Antineoplastic Agents Binding Cancer Biology Cells Chemicals Childhood Acute Myeloid Leukemia Chimeric Proteins Chromatin Chromosomal translocation Clinical Trials Complex Crystallization Cytogenetics Development Diagnosis Disease Drug Kinetics Drug Targeting EZH2 gene Enzyme Inhibition Epigenetic Process Euchromatin Experimental Leukemia Gene Expression Genes Genetic Transcription Goals Histones Human Impairment In Vitro Lead Leukemic Cell Link Lung Malignant Neoplasms Malignant neoplasm of prostate Metabolic Methylation Modeling Modification Mus Nuclear Receptors Oncogenes Oncogenic Outcome Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Play Point Mutation Prognosis Property Protein Family Proteomics Refractory Relapse Reporting Research Resolution Role SET Domain Series Structure Testing Xenograft Model anti-cancer base chemotherapy clinical application cohort design efficacy study efficacy testing histone methyltransferase improved in vitro activity in vivo inhibitor innovation leukemia member novel novel anticancer drug novel therapeutics patient derived xenograft model pediatric patients rational design receptor binding scaffold screening small molecule small molecule inhibitor tumor growth tumorigenesis

项目摘要

Epigenetic abnormalities are very common in human cancers and play a critical role in tumorigenesis via dysregulation of gene expression and by affecting chromatin function. Inhibition of enzymes involved in epigenetic modifications has been recognized as a very attractive approach to develop novel drugs. Histone methyltransferases (HMTs) emerged as very promising class of anti-cancer drug targets and several recently developed inhibitors have been advanced to clinical trials, including inhibitors of DOT1L, EZH2 and PRMT5. These examples clearly emphasize significance of developing HMT inhibitors as novel anti-cancer drugs. In this project we propose to develop inhibitors of NSD1 histone methyltransferase. Translocation of NSD1 gene with Nup98 leading to Nup98-NSD1 fusion protein is found in pediatric acute myeloid leukemia patients with very poor prognosis. It has been validated that histone-methyltrasferase activity of NSD1 SET domain is required for oncogenic activity of Nup98-NSD1. To date, no NSD1 inhibitors have been described. We have identified small molecule compounds binding to NSD1 SET domain and employed extensive medicinal chemistry to significantly improve their activity. We developed potent cell-active NSD1 inhibitors blocking proliferation of Nup98-NSD1 cells. For our lead compound, we also demonstrated efficacy in animal model of Nup98-NSD1 leukemia. In this proposal, we will develop and optimize two classes of NSD1 inhibitors with two different mechanisms of action. We will optimize potency and drug-like properties of NSD1 inhibitors and perform extensive efficacy studies in animal models. In addition, our goal is to develop patient-derived xenograft (PDX) model of Nup98-NSD1 leukemia for efficacy studies. Our project will result in potent drug-like NSD1 inhibitors to be used as chemical probes and novel pharmacologic agents for acute leukemia.

表观遗传异常在人类癌症中非常常见，并且通过以下途径在肿瘤发生中起关键作用：基因表达失调和影响染色质功能。抑制酶参与表观遗传修饰已被认为是开发新药的非常有吸引力的方法。组蛋白甲基转移酶（HMTs）是一类非常有前途的抗癌药物靶点，已开发的抑制剂已进入临床试验，包括DOT 1 L、EZH 2和PRMT 5的抑制剂。这些例子清楚地强调了开发HMT抑制剂作为新型抗癌药物的重要性。在这个项目中，我们建议开发NSD 1组蛋白甲基转移酶的抑制剂。NSD 1的转运在儿童急性髓性白血病患者中发现了导致Nup 98-NSD 1融合蛋白的Nup 98基因预后很差已经证实，NSD 1 SET结构域的组蛋白甲基转移酶活性是 Nup 98-NSD 1的致癌活性所必需的。迄今为止，尚未描述NSD 1抑制剂。我们有鉴定了与NSD 1 SET结构域结合的小分子化合物，并使用了广泛的药物化学，以显着提高其活性。我们开发了有效的细胞活性NSD 1抑制剂， Nup 98-NSD 1细胞的增殖。对于我们的先导化合物，我们还证明了在动物模型中的有效性。 Nup 98-NSD 1白血病。在这个建议中，我们将开发和优化两类NSD 1抑制剂，不同的作用机制。我们将优化NSD 1抑制剂的效力和药物样性质，在动物模型中进行广泛的功效研究。此外，我们的目标是开发患者衍生的 Nup 98-NSD 1白血病的异种移植（PDX）模型用于功效研究。我们的项目将产生一种强效的药物， NSD 1抑制剂可用作急性白血病的化学探针和新型药物。