Novel drug to treat poor prognosis AML

治疗预后不良的 AML 的新药

• 批准号: 10290199
• 负责人: Reuben Kapur
• 金额: $ 23.47万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-02 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290199
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Adult; Biological; Biological Assay; Biology; Cell Culture Techniques; Cells; Clinic; Clinical Trials; Complex; Cyclic GMP; Data; Disease remission; Drug resistance; Gatekeeping; Goals; Growth; Hematopoietic stem cells; High Prevalence; In Vitro; Incidence; Karyotype; Leukemic Cell; Membrane; Modeling; Mus; Mutate; Mutation; Myeloproliferative disease; Naphthyridines; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phosphotransferases; Point Mutation; Positioning Attribute; Prognosis; Prognostic Marker; Receptor Activation; Receptor Protein-Tyrosine Kinases; Recurrent disease; Refractory; Relapse; Reporting; Resistance; Resistance development; Series; Small Business Innovation Research Grant; Structure-Activity Relationship; Therapeutic; Translating; United States Food and Drug Administration; acute myeloid leukemia cell; analog; antileukemic activity; base; cell transformation; clinically significant; fetal liver kinase-2; hematopoietic stem cell self-renewal; high risk; in vivo; inhibitor/antagonist; leukemia treatment; mouse model; mutant; nanomolar; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; resistance mechanism; response; standard of care; targeted treatment

PROJECT SUMMARY/ABSTRACT The incidence of acute myeloid leukemia (AML) has been on the rise. Activating mutations in the fms like tyrosine kinase 3 (FLT3) are present in 25-30% of AML, ~10% of myelodysplastic (MDS) and 5-6% of acute lymphoblastic leukemia (ALL) patients. The common mutations include missense point mutations in the kinase domain, in frame deletions and internal tandem duplications (ITD) in the juxta membrane domain leading to constitutive activation of the receptor tyrosine kinase (RTK) activity. FLT3-ITD is present in ~25% AML patients with normal karyotype and is considered an independent prognostic marker. Patients with FLT3-ITD mutation are at a higher risk of disease relapse and reduced overall 5-year survival. Activating mutations of FLT3 contribute to deregulated proliferation of hematopoietic progenitor cells leading to myeloproliferative neoplasm (MPN). We and others have shown that co-occurrence of mutations that enhance the self-renewal of hematopoietic stem cells (HSC) can transform these cells into AML.However, despite the high prevalence rate and the clinical significance of FLT3 mutations in the pathogenesis of AML, there are limited options for targeted therapy. In 2017, Midostaurin (Rydapt), a multi-kinase inhibitor became the first targeted therapy to be approved by food and drug administration (FDA) for the treatment of AML, followed by Gilteritinib (Xospata), a FLT3 and AXL1 specific inhibitor in 2018. Additional experimental drugs specific for mutant FLT3 in various stages of clinical trials including Quizartinib and Crenolanib have also been described, although they are known to develop both intrinsic and acquired resistance in response to FLT3 targeted therapy the intrinsic resistance in AML to therapy with FLT3 directed inhibitors depends on the presence of co-occurring mutations acquired resistance is due to activation of parallel survival pathways and/or acquisition of secondary mutations in FLT3-ITD. More recently, emergence of RAS mutations has been reported in AML patients treated with Gilteritinib. Thus, there is a critical unmet need to identify and develop potent and selective inhibitor(s) for mutant FLT3 to provide additional therapeutic options for treating AML patients with these mutations. To this end, we have recently identified a novel class of naphthyridine based FLT3 inhibitors that not only selectively target FLT3-ITD at sub-nanomolar concentrations but are also effective against the drug resistance conferring secondary mutations acquired in response to targeted therapy. Based on our preliminary data, we hypothesize that in comparison to recently FDA approved FLT3 inhibitors, including Gilteritinib, we have identified novel and potent drugs with inhibitory activity against FLT3-ITD as well as gatekeeper mutations of FLT3 for a more robust and durable AML treatment. We will utilize two of these inhibitors (KRX-101 & KRX-107; also defined as HSN608 & HSN748, respectively) to further characterize its biological impact on primary de novo AMLs, drug resistant AMLs as well as relapsed/refractory AMLs bearing FLT3 mutations along with other co-occurring mutations.

项目总结/摘要 急性髓细胞白血病（AML）的发病率一直呈上升趋势。激活fms中的突变，如酪氨酸 激酶3（FLT 3）存在于25-30%的AML、~10%的骨髓增生异常（MDS）和5-6%的急性淋巴细胞白血病（ALL）中。 白血病（ALL）患者。常见的突变包括激酶结构域中的错义点突变， 框架缺失和内部串联重复（ITD）在膜结构域，导致组成性 受体酪氨酸激酶（RTK）活性的激活。FLT 3-ITD存在于约25%的AML患者中， 核型，并被认为是一个独立的预后标志物。携带FLT 3-ITD突变的患者， 疾病复发的风险和总体5年生存率降低。FLT 3的激活突变有助于 造血祖细胞增殖失调导致骨髓增生性肿瘤（MPN）。我们 和其他人已经表明，增强造血干细胞自我更新的突变的共同出现， 造血干细胞（HSC）可以将这些细胞转化为AML。然而，尽管AML的患病率很高， FLT 3突变在AML发病机制中的重要性，靶向治疗的选择有限。在 2017年，多激酶抑制剂米多普汀（Rydapt）成为首个获得食品批准的靶向治疗药物 和药物管理局（FDA）用于治疗AML，其次是Gilteritinib（Xospata），FLT 3和AXL 1 在2018年的特定抑制剂。在不同临床阶段对突变型FLT 3具有特异性的其他实验药物 包括Quizartinib和Crenolanib在内的试验也有描述，尽管已知它们同时开发了 对FLT 3靶向治疗的内在和获得性耐药性AML对治疗的内在耐药性 与FLT 3定向抑制剂依赖于共同发生的突变的存在，获得性耐药是由于 平行存活途径的激活和/或FLT 3-ITD中继发突变的获得。最近， 在接受Gilteritinib治疗的AML患者中报告了RAS突变的出现。因此，有一个关键的 未满足的需求，以确定和开发突变型FLT 3的有效和选择性抑制剂， 治疗具有这些突变的AML患者的治疗选择。为此，我们最近确定了一个 新型的基于萘啶的FLT 3抑制剂，其不仅以亚纳摩尔浓度选择性靶向FLT 3-ITD， 浓度，但也有效地对抗药物抗性，赋予获得的继发性突变， 对靶向治疗的反应。根据我们的初步数据，我们假设与最近的FDA相比， 批准的FLT 3抑制剂，包括Gilteritinib，我们已经确定了具有抑制活性的新型强效药物 针对FLT 3-ITD以及FLT 3的看门人突变，用于更稳健和持久的AML治疗。我们 将利用这些抑制剂中的两种（KRX-101和KRX-107;也分别定义为HSN 608和HSN 748）， 进一步表征其对原发性新发AML、耐药AML以及 携带FLT 3突变沿着其他共发生突变的复发性/难治性AML。