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.

项目总结