Novel drug to treat poor prognosis AML

治疗预后不良的 AML 的新药

• 批准号: 10443887
• 负责人: Reuben Kapur
• 金额: $ 18.03万
• 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/10443887
• 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; FLT3 gene; 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; hematopoietic stem cell self-renewal; high risk; in vivo; inhibitor; leukemia treatment; mouse model; mutant; nanomolar; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; prognostic of survival; 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.

项目概要/摘要 急性髓系白血病（AML）的发病率呈上升趋势。激活 fms 中的突变，如酪氨酸 激酶 3 (FLT3) 存在于 25-30% 的 AML、约 10% 的骨髓增生异常 (MDS) 和 5-6% 的急性淋巴细胞白血病中 白血病（ALL）患者。常见的突变包括激酶结构域的错义点突变， 近膜结构域中的框架缺失和内部串联重复（ITD）导致组成型 激活受体酪氨酸激酶（RTK）活性。 FLT3-ITD 存在于约 25% 正常的 AML 患者中 核型并被认为是独立的预后标志物。 FLT3-ITD 突变患者的患病率较高 疾病复发的风险和总体 5 年生存率降低。 FLT3 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 等人表明，增强造血干自我更新的突变同时发生 细胞（HSC）可以将这些细胞转化为 AML。然而，尽管患病率很高且临床 尽管 FLT3 突变在 AML 发病机制中的重要性，但靶向治疗的选择有限。在 2017年，多激酶抑制剂Midostaurin（Rydapt）成为第一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，随后是 Gilteritinib (Xospata)、FLT3 和 AXL1 2018年的特异性抑制剂。针对突变型FLT3的其他实验药物处于临床各个阶段 还描述了包括 Quizartinib 和 Crenolanib 在内的试验，尽管已知它们都开发了这两种药物 FLT3 靶向治疗的内在耐药性和获得性耐药性 AML 对治疗的内在耐药性 FLT3定向抑制剂取决于同时发生的突变的存在，获得性耐药是由于 平行生存途径的激活和/或 FLT3-ITD 二次突变的获得。最近， 据报道，接受 Gilteritinib 治疗的 AML 患者出现了 RAS 突变。因此，有一个关键的 识别和开发突变型 FLT3 的有效和选择性抑制剂的未满足需求，以提供额外的 治疗携带这些突变的 AML 患者的治疗选择。为此，我们最近确定了一个 基于萘啶的新型 FLT3 抑制剂，不仅可以在亚纳摩尔级选择性靶向 FLT3-ITD 浓度，但也能有效对抗耐药性，从而获得二次突变 对靶向治疗的反应。根据我们的初步数据，我们假设与最近 FDA 已批准的 FLT3 抑制剂，包括 Gilteritinib，我们已经确定了具有抑制活性的新型有效药物 针对 FLT3-ITD 以及 FLT3 的看门人突变，以获得更强大和持久的 AML 治疗。我们 将利用其中两种抑制剂（KRX-101 和 KRX-107；也分别定义为 HSN608 和 HSN748） 进一步表征其对原发性新发 AML、耐药 AML 以及 携带 FLT3 突变以及其他同时发生的突变的复发/难治性 AML。

项目成果

Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.

• DOI: 10.1016/j.ymthe.2022.04.009
• 发表时间: 2022-07-06
• 期刊: MOLECULAR THERAPY
• 影响因子: 12.4
• 作者: Ramdas, Baskar;Yuen, Lisa Deng;Palam, Lakshmi Reddy;Patel, Roshini;Pasupuleti, Santhosh Kumar;Jideonwo, Victoria;Zhang, Ji;Maguire, Callista;Wong, Eric;Kanumuri, Rahul;Zhang, Chujing;Sandusky, George;Chan, Rebecca J.;Zhang, Chi;Stieglitz, Elliot;Haneline, Laura;Kapur, Reuben
• 通讯作者: Kapur, Reuben