Development of an irreversible covalent inhibitor of FMS-like tyrosine kinase receptor 3 for treating acute myeloid leukemia

项目摘要 急性髓性白血病（AML）是骨髓中造血前体细胞的恶性疾病， 占所有癌症的1%。AML通常在生命后期被诊断出来 60岁及以上的个体的长期存活率仅为5- 15%。细胞遗传学分析 诊断时的异常细胞已被证明是治疗成功的极好指标， 预后几种突变与AML相关，其中最常见的是FMS样突变。 酪氨酸激酶3（FLT 3）基因导致促进细胞因子非依赖性AML细胞存活， 增殖目前有两种FDA批准的酪氨酸激酶抑制剂（TKI）用于治疗患有以下疾病的患者： FLT 3突变;然而，研究表明，超过60%的患者对这些药物缺乏反应。 以及由于脱靶毒性引起的许多副作用。BridGene Biosciences正在开发一种新的 化学实体作为FLT 3的小分子共价抑制剂，以解决FDA的限制， 已批准的FLT 3抑制剂和正在开发的抑制剂。共价FLT 3抑制剂具有更高的效力， 选择性和比目前的非共价FLT 3抑制剂更长的停留时间， 突变，从而为AML提供更有效和安全的治疗选择。BridGene Biosciences的FLT 3 抑制剂，称为BGS 2456，已经证明了对AML细胞系的选择性体外生长抑制活性 由不同的FLT 3致癌突变体驱动。这些初步努力为实现 执行拟议的第一阶段计划，目的是获得使用BGS 2456的概念验证 作为AML的最佳FLT 3抑制剂。目的1的目的是增强药物的类药物性质。 BGS 2456通过药物化学方法。合成衍生物（目标1A）将根据 预先确定的效价、选择性（目标1B）和其他一些性质的指标，以评估其潜力 使用标准体外测定法确定其成为药物（目标1C）。顶级衍生品将提前 目的2，其集中于使用AML细胞表征衍生物的体外效力和选择性 线（目的2A和2B）和评估血液毒性（目的2C）。一个单一的铅衍生物将提前到目标3， 其旨在获得先导BGS 2456衍生物在治疗中的用途的体内概念验证 急性髓细胞白血病最初，将进行PK和耐受性研究（目的3A）以告知给药，然后将 评估体内疗效，定义为生存期延长和疾病进展减少 与gilteritinib（FDA批准的FLT 3 TKI）相比，在AML小鼠模型中（Aim 3B）。成功完成 拟议的第一阶段计划将支持第二阶段项目，重点是完成关键的 药理学和安全性评估研究，以生成使用 治疗AML的新型共价FLT 3抑制剂。

PROJECT SUMMARY Acute myeloid leukemia (AML), a malignant disease of hematopoietic precursor cells in the bone marrow, is one of the most common cancers in adults accounting for 1% of all cancers. AML is typically diagnosed later in life with individuals 60 and older having a long-term survival rate of merely 5-15%. Cytogenic analysis of the abnormal cells at the time of diagnosis has proven to be an excellent indicator of treatment success as well as prognosis. Several mutations are associated with AML with the most common ones being in the FMS-like tyrosine kinase 3 (FLT3) gene leading to the promotion of cytokine independent AML cell survival and proliferation. There are currently two FDA-approved tyrosine kinase inhibitors (TKIs) for treating patients with FLT3 mutations; however, studies have shown a significant lack of response to these drugs in upwards of 60% of patients and a number of side effects due to off-target toxicities. BridGene Biosciences is developing a new chemical entity to serve as a small-molecule covalent inhibitor of FLT3 in order to address the limitations of FDA- approved FLT3 inhibitors and those under development. A covalent FLT3 inhibitor has higher potency, selectivity, and longer residence time than current non-covalent FLT3 inhibitors, and treat drug-resistant mutations, thus providing a more effective and safe treatment option for AML. BridGene Biosciences’ FLT3 inhibitor, known as BGS2456, has demonstrated selective in vitro growth inhibition activity against AML cell lines driven by different FLT3 oncogenic mutants. These preliminary efforts provide significant support for the execution of the proposed Phase I program with the goal of obtaining proof-of-concept for the use of BGS2456 as a best-in-class FLT3 inhibitor for AML. The objective of Aim 1 is to enhance the drug-like properties of BGS2456 through a medicinal chemistry approach. Synthesized derivatives (Aim 1A) will be ranked according to pre-determined metrics for potency, selectivity (Aim 1B), and a few other properties to assess their potential to become drugs (Aim 1C) as determined using standard in vitro assays. The top derivatives will be advanced to Aim 2, which is focused on characterizing the in vitro potency and selectivity of the derivatives using AML cell lines (Aims 2A & 2B) and assessing hematotoxicity (Aim 2C). A single lead derivative will be advanced to Aim 3, which is geared toward obtaining in vivo proof-of-concept for the use of a lead BGS2456 derivative in treating AML. Initially, PK and tolerability studies (Aim 3A) will be executed to inform dosing then the derivative will be assessed for in vivo efficacy, which will be defined as enhanced survival and reduction in disease progression compared to gilteritinib (an FDA-approved FLT3 TKI) in an AML mouse model (Aim 3B). Successful completion of the proposed Phase I program will support a Phase II project that is focused on completing key pharmacological and safety assessment studies in order to generate a target product profile for the use of the novel covalent FLT3 inhibitor in treating AML.