Targeting NSD1 in leukemia

表观遗传学异常在人类癌症中非常常见，并通过以下途径在肿瘤发生中发挥关键作用 基因表达失调，并通过影响染色质功能。抑制与之相关的酶 表观遗传修饰已被认为是开发新药的一种非常有吸引力的方法。组蛋白 甲基转移酶(HMTs)是近年来出现的一类非常有前景的抗癌药物靶点。 已开发的抑制剂已进入临床试验，包括DOT1L、EZH2和PRMT5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NSD1组蛋白甲基转移酶的抑制剂。NSD1的易位 儿童急性髓系白血病患者中发现Nup98导致Nup98-NSD1融合蛋白的基因 预后非常差。已证实NSD1 SET结构域的组蛋白甲基转移酶活性为 Nup98-NSD1的致癌活性所需。到目前为止，还没有描述过NSD1抑制剂。我们有 鉴定与NSD1 SET结构域结合的小分子化合物及其广泛的药用价值 来显著提高他们的活跃度。我们开发了有效的细胞活性NSD1抑制剂阻断 Nup98-NSD1细胞增殖情况。对于我们的先导化合物，我们还在动物模型中证明了其有效性。 Nup98-NSD1白血病。在这个方案中，我们将开发和优化两类NSD1抑制剂，其中包括两个 不同的作用机制。我们将优化NSD1抑制剂的效力和类药物特性 在动物模型中进行广泛的疗效研究。此外，我们的目标是开发患者派生的 Nup98-NSD1白血病异种移植模型的疗效研究我们的项目将产生强效类药物 NSD1抑制剂作为化学探针和新型药理药物治疗急性白血病。

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.