Novel drug to treat poor prognosis AML

项目摘要/摘要 急性髓系白血病(AML)的发病率一直呈上升趋势。激活FMS中类似酪氨酸的突变 25%-30%的AML、约10%的骨髓增生异常(MDS)和5%-6%的急性淋巴母细胞(ALL)中存在激酶3(Flt3) 白血病(ALL)患者。常见的突变包括激酶域的错义点突变，在 膜结构域中的帧缺失和内部串联复制(ITD)导致构造性 激活受体酪氨酸激酶(RTK)活性。约25%的正常AML患者存在Flt3-ITD 核型，被认为是一个独立的预后标志。携带Flt3-ITD突变的患者处于较高水平 疾病复发的风险和总的5年存活率降低。Flt3基因的激活突变有助于 造血祖细胞增殖失控导致骨髓增生性肿瘤(MPN)。我们 和其他人的研究表明，共同出现的增强造血干细胞自我更新的突变 细胞(HSC)可将这些细胞转化为急性髓细胞白血病(AML)，然而，尽管发病率高，临床上 Flt3突变在AML发病机制中的意义，靶向治疗的选择有限。在……里面 2017年，多激酶抑制剂米多妥林(Rydapt)成为首个被食品批准的靶向疗法 和药物管理局(FDA)治疗AML，紧随其后的是Gilteritinib(Xospata)、a Flt3和AXL1 2018年的特定抑制剂。临床不同阶段针对突变Flt3的额外实验药物 包括Quizartinib和Crenolanib在内的试验也被描述过，尽管它们都是已知的 Flt3靶向治疗的内在和获得性耐药急性髓系白血病的内在耐药 使用Flt3定向抑制剂取决于共生突变的存在，获得性耐药性是由于 Flt3-ITD中平行生存通路的激活和/或继发性突变的获得。最近， 有报道称，使用Gilteritinib治疗的AML患者中出现了RAS突变。因此，有一个关键的 尚未满足的需求：为突变的Flt3确定和开发有效的选择性抑制剂(S)，以提供额外的 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 一类新型的基于萘啶的Flt3抑制剂，不仅选择性地靶向亚纳米分子的Flt3-ITD 浓度，但也有效地对抗导致继发性突变的耐药性 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Flt3抑制剂，包括Gilteritinib，我们已经确定了具有抑制活性的新的有效药物 针对Flt3-ITD以及Flt3的把关人突变，以实现更强大和持久的AML治疗。我们 将使用其中两种抑制剂(KRX-101和KRX-107；也分别定义为HSN608和HSN748)来 进一步表征其对原发原发AML、耐药AML以及 复发/难治性急性髓细胞白血病携带Flt3突变以及其他共生突变。

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.