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

开发用于治疗急性髓性白血病的 FMS 样酪氨酸激酶受体 3 的不可逆共价抑制剂

• 批准号: 10081364
• 负责人: Ping Cao
• 金额: $ 29.89万
• 依托单位: BRIDGENE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081364
• 关键词: Abnormal Cell; Accounting; Acute Myelocytic Leukemia; Address; Adult; Benchmarking; Biochemical; Biological Assay; Biological Sciences; Bioluminescence; Bone Marrow; Cancer Control; Cell Line; Cell Proliferation; Cell Survival; Cell-Free System; Cells; Chemicals; Chromosome abnormality; Clinical; Covalent Interaction; Development; Diagnosis; Disease; Disease Progression; Disease remission; Dose; Drug resistance; Effectiveness; Exhibits; FDA approved; Foundations; Genes; Goals; Growth; Hematopoiesis; Hematopoietic; Human; In Vitro; Individual; Lead; Leukemic Cell; Life; Liver; Malignant - descriptor; Malignant Neoplasms; Measures; Mus; Mutation; Myelosuppression; Oncogenic; Patient-Focused Outcomes; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Phosphotransferases; Plasma Proteins; Play; Property; Receptor Protein-Tyrosine Kinases; Recovery; Regulation; Resistance; Solid; Solubility; Structure-Activity Relationship; Survival Rate; Therapeutic; Therapeutic Index; Time; Toxic effect; Treatment Failure; Tyrosine Kinase Inhibitor; Validation; Vascular Endothelial Growth Factor Receptor-1; acute myeloid leukemia cell; base; cancer cell; chemotherapy; cytokine; disease heterogeneity; efficacy study; experience; fetal liver kinase-2; improved; in vitro Assay; in vivo; inhibitor/antagonist; kinase inhibitor; lead-binding proteins; mouse model; mutant; novel; outcome forecast; precursor cell; programs; relapse patients; residence; resistance mutation; response; safety assessment; side effect; small molecule; standard of care; success; targeted treatment; therapy outcome

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.

项目摘要 急性髓样白血病（AML）是骨髓中造血前体细胞的恶性疾病，是一种 成年人最常见的癌症占所有癌症的1％。 AML通常在以后的生活中被诊断 60岁及以上的个体长期存活率仅为5-15％。细胞遗传学分析 诊断时异常细胞已被证明是治疗成功的绝佳指标 预后。几种突变与AML相关，其中最常见的突变是在FMS样中 酪氨酸激酶3（FLT3）基因，导致促进细胞因子独立AML细胞存活和 目前有两个FDA批准的酪氨酸激酶抑制剂（TKI）用于治疗患者 FLT3突变；但是，研究表明，对这些药物的反应显着缺乏60％以上 患者和由于脱靶毒性引起的许多副作用。 Bridgene Biosciences正在开发一个新的 化学实体是FLT3的小分子共价抑制剂，以解决FDA-的局限性 批准的FLT3抑制剂和正在开发的抑制剂。共价FLT3抑制剂具有较高的效力， 选择性和停留时间比当前的非共价FLT3抑制剂，并治疗耐药性 突变，从而为AML提供了更有效，更安全的治疗选择。 Bridgene Biosciences的FLT3 抑制剂（称为BGS2456）已证明对AML细胞系的体外生长抑制活性选择性 由不同的FLT3致癌突变体驱动。这些初步努力为 执行建议的I期计划，目的是获得使用BGS2456的概念验证证明 作为AML的一流FLT3抑制剂。目标1的目的是增强类似药物的特性 BGS2456通过医学化学方法。合成的衍生物（AIM 1A）将根据 预先确定的效能指标，选择性（目标1B）和其他一些属性，以评估其潜力 使用标准体外测定确定的药物（AIM 1C）。顶级衍生品将是先进的 AIM 2，专注于使用AML单元格的体外效力和选择性表征衍生物的选择性 线（AIMS 2A和2B）和评估血毒性（AIM 2C）。单个铅衍生物将被推进到AIM 3， 旨在获得用于使用铅BGS2456衍生物治疗的体内概念概念证明 AML。最初，将执行PK和耐受性研究（AIM 3A）以告知给药，然后衍生物将是 评估体内效率，该效率将定义为增强的存活率和疾病进展的降低 与AML小鼠模型（AIM 3B）中的Gilteritinib（AIM 3B）中的Gilteritinib（FDA批准的FLT3 TKI）相比。成功完成 拟议的第一阶段计划将支持一个重点完成密钥的II阶段项目 药理和安全评估研究是为了生成目标产品概况以使用 新型共价FLT3抑制剂在治疗AML中。